WO2001005380A1 - Sustained release compositions, process for producing the same and use thereof - Google Patents

Sustained release compositions, process for producing the same and use thereof Download PDF

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Publication number
WO2001005380A1
WO2001005380A1 PCT/JP2000/004683 JP0004683W WO0105380A1 WO 2001005380 A1 WO2001005380 A1 WO 2001005380A1 JP 0004683 W JP0004683 W JP 0004683W WO 0105380 A1 WO0105380 A1 WO 0105380A1
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WO
WIPO (PCT)
Prior art keywords
salt
acid
sustained
lactic acid
polymer
Prior art date
Application number
PCT/JP2000/004683
Other languages
French (fr)
Japanese (ja)
Inventor
Yasutaka Igari
Yoshio Hata
Kazumichi Yamamoto
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL00352499A priority Critical patent/PL352499A1/en
Priority to DE60034568T priority patent/DE60034568T2/en
Priority to AU58530/00A priority patent/AU5853000A/en
Priority to IL14741700A priority patent/IL147417A0/en
Priority to SK34-2002A priority patent/SK342002A3/en
Priority to HU0202880A priority patent/HUP0202880A3/en
Priority to NZ516466A priority patent/NZ516466A/en
Priority to KR1020027000546A priority patent/KR20020012312A/en
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to BR0012400-1A priority patent/BR0012400A/en
Priority to US10/019,786 priority patent/US7265157B1/en
Priority to CA002378714A priority patent/CA2378714A1/en
Priority to EP00944418A priority patent/EP1197208B1/en
Priority to MXPA02000461A priority patent/MXPA02000461A/en
Publication of WO2001005380A1 publication Critical patent/WO2001005380A1/en
Priority to NO20020084A priority patent/NO20020084L/en
Priority to HK02103567.5A priority patent/HK1042237A1/en
Priority to US11/782,707 priority patent/US20080014237A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • the present invention relates to a sustained-release preparation of a physiologically active substance and a method for producing the same.
  • JP-A-7-97334 discloses a sustained-release preparation comprising a physiologically active peptide or a salt thereof and a biodegradable polymer having a free carboxyl group at a terminal, and a method for producing the same.
  • GB2209937, GB2234169, GB2234896, GB2257909 and EP 62617 OA2 disclose biodegradable polymers comprising separately prepared peptides and water-insoluble salts such as protein pamoate. -Based compositions or processes for their production are disclosed.
  • W-95 No. 15767 discloses embolic acid salt (pamoate) of cetrorelix (LH-RH angyu gonist) and a method for producing the same. It is described that the release of the peptide is similar to that of pamoate alone when encapsulated in a polymer. Disclosure of the invention
  • a novel composition which contains a high content of a physiologically active substance and suppresses the initial excessive release, thereby realizing a stable release rate over a long period of time (preferably about 6 months or more).
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a bioactive substance and a hydroxynaphthoic acid coexist when forming a composition, whereby the bioactive substance is contained in the composition at a high content. If both are encapsulated in the lactic acid-glycolic acid polymer, prepare it under the condition that the lactic acid-dalicholic acid polymer is not present. Bioactive substance is released at a rate different from the release rate of the bioactive substance from the composition formed from the bioactive substance and hydroxynaphthoic acid, and the release rate is the characteristic of lactic acid-glycolic acid polymer.
  • the product of the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal lipoxyl group amount (micromol) per unit mass (gram) of the lactic acid-glycolic acid polymer is not less than 1,200,000 and 3,000,000 It has been found that a better sustained-release preparation can be provided by using the following lactic acid-glycolic acid polymer. As a result of further research, the present invention has been completed.
  • It contains a physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof, and the weight average molecular weight of the lactic acid-glycolic acid polymer and the A sustained-release composition having a product of terminal carboxyl group amount (micromol) per unit mass (gram) of not less than 1,200,000 and not more than 3,00000,
  • sustained-release composition according to the above (1), wherein the physiologically active substance or a salt thereof is slightly water-soluble or water-soluble.
  • a physiologically active substance or a salt thereof is mixed and dispersed in an organic solvent solution containing a lactic acid-glycolic acid polymer or a salt thereof and hydroxynaphthoic acid or a salt thereof, and then the organic solvent is removed.
  • Prostate cancer Prostatic hyperplasia comprising the sustained release composition according to (3) above, Prevention of endometriosis, uterine fibroids, uterine fibroids, precocious puberty, dysmenorrhea or breast cancer, treatment or contraceptive,
  • a sustained-release composition comprising a physiologically active substance or a salt thereof, 1-hydroxy-2-naphthoic acid or a salt thereof, and a biodegradable polymer or a salt thereof.
  • a solution containing a physiologically active substance or a salt thereof is used as an internal aqueous phase, and a solution containing a lactic acid-glycolic acid polymer and hydroxynaphthoic acid or a salt thereof is used as an oil phase.
  • a WZO-type emulsion is prepared in which a liquid containing hydroxynaphthoic acid or a salt thereof is used as an internal aqueous phase, and a solution containing a physiologically active substance or a salt thereof and a solution containing a lactic acid-glycolic acid polymer or a salt thereof is used as an oil phase.
  • the physiologically active substance used in the present invention is not particularly limited as long as it is pharmacologically useful, and may be a non-peptide compound or a peptide compound.
  • the non-peptidic compound include agonist, angonist, and a compound having an enzyme inhibitory action.
  • a bioactive peptide is preferable, and a bioactive peptide having a molecular weight of about 300 to about 40,000, preferably about 400 to about 30,000, and more preferably about 500 to about 20,000 is used.
  • bioactive peptide examples include luteinizing hormone-releasing hormone (LH-RH), insulin, somatostatin, growth hormone, growth hormone-releasing hormone (GH-RH), prolactin, erythropoietin, corticosteroids, melanocyte stimulation.
  • LH-RH luteinizing hormone-releasing hormone
  • insulin insulin
  • somatostatin growth hormone
  • G-RH growth hormone-releasing hormone
  • prolactin prolactin
  • erythropoietin corticosteroids
  • melanocyte stimulation examples include luteinizing hormone-releasing hormone (LH-RH), insulin, somatostatin, growth hormone, growth hormone-releasing hormone (GH-RH), prolactin, erythropoietin, corticosteroids, melanocyte stimulation.
  • Hormones thyroid hormone releasing hormone, thyroid stimulating hormone, luteinizing hormone, follicle stimulating hormone, vasopressin, oxitocin, calcitonin, gastrin, secretin, pancreozymine, cholecystokinin, angiotensin, human placental lactogen, human Chorionic gonadotropin, enkephalin, endorphin, kyotorphin, tuftsin, thymopoietin, thymosin, thymothymulin, thymic factor, blood thymic factor, tumor necrosis factor, colo -Inducible factors, motilin, dinorphin, bombesin, neurotensin, cellulin, bradykinin, atrial natriuretic factor, nerve growth factor, cell growth factor, neurotrophic factor, peptides having endothelin antagonism, etc. Derivatives, as well as fragments or derivatives of these fragments.
  • the physiologically active substance used in the present invention may be itself or a pharmacologically acceptable salt.
  • salts include, when the physiologically active substance has a basic group such as an amino group, an inorganic acid (also referred to as an inorganic free acid) (eg, carbonic acid, bicarbonate, hydrochloric acid, sulfuric acid, nitric acid, nitric acid, boric acid) Etc.) and salts with organic acids (also referred to as organic free acids) (eg, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.).
  • an inorganic acid also referred to as an inorganic free acid
  • organic acids also referred to as organic free acids
  • an inorganic base also referred to as an inorganic free base
  • an organic base eg, organic amines such as triethylamine, basic amino acids such as arginine, etc.
  • the physiologically active peptide may form a metal complex compound (eg, a copper complex, a zinc complex, etc.).
  • Preferred examples of the physiologically active peptide include LH-RH derivatives, Mon-dependent diseases, especially sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, none LH-RH derivatives effective for menstrual disorders, premenstrual syndrome, multi-ovarian ovary syndrome, and other sex hormone-dependent diseases and contraception (or infertility if the rebound effect after drug withdrawal is used) Or a salt thereof.
  • LH-RH derivatives or salts thereof that are effective for benign or malignant tumors that are sex hormone-independent but LH-RH sensitive are also included.
  • LH-RH derivative or its salt include, for example, Treatment with GnRH analog: Contraversies and perspectives [The Zirrete Non-Bubbling Group Co., Ltd. (The Parthenon Publishing Group) 1996)], Japanese Patent Application Laid-Open No. 3-503165, Japanese Patent Application Laid-Open Nos. 3-101695, 7-97334 and 8-259460, and the like. .
  • LH-RH derivatives include LH-RH agonists and LH-RH angelists.
  • LH-RH antagonists include, for example, a compound represented by the general formula [I] X-D2Nal-D4ClPhe-D3Pal-Ser -AB-Leu-C-Pro-DAlaNH 2
  • X is N (4H2-furoyUGly or NAc
  • A is a residue selected from NMeTyr, Tyr, Aph (Atz), NMeAph (Atz)
  • B is DLys (Nic), DCit, DLys (AzaglyNic) , DLys (AzaglyFur), DhArg (Et 2 ), a residue selected from DAph (Atz) and U3 ⁇ 4hCi, and C represents Lys (Nisp), Arg or hArg (Et 2 ), respectively.
  • a salt thereof is used.
  • Y represents a residue selected from DLeu, DAla, DT ⁇ , DSer (tBu), D2Nal and! His (ImBzl), and Z represents NH-C 2 H 5 or Gly-NH 2 3 ⁇ 4, respectively.
  • a physiologically active peptide represented by or a salt thereof is used.
  • Table Y in is DLeu
  • Z is at HC 2 H 5 is a base peptide (i.e., 5- oxo-Pro- His- Trp- Ser -Tyr- DLeu-Leu- Arg-Pro- NH- C 2 H 5 Is are preferred.
  • NMeAph (Atz): N-methyl- [5 '-(3'-amino- ⁇ - 2', 4'-triazolyl)] phenylalanine residue
  • DHis (ImBzl): One D—Histidine
  • amino acids when indicated by abbreviations, IUPAC-IUB Commission 'Ob' noisyochemikare 'Commission on Biochemical Nomenclature' (European Journal of Biochemistry) Vol. 138, pp. 9-37 (1984)) or abbreviations commonly used in the relevant field.
  • amino acids may have optical isomers, L-forms shall be indicated unless otherwise specified. I do.
  • 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid and 2-hydroxy-2-naphthoic acid in which a carbonyl group and a hydroxyl group are bonded to adjacent carbon atoms of the naphthylene ring Hydroxy-1-naphthoic acid is preferred.
  • Hydroxynaphthoic acid may be a salt.
  • Salts include, for example, inorganic bases (eg, Salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, etc.) and organic bases (eg, organic amines such as triethylamine, basic amino acids such as arginine), or Examples include salts and complex salts with transition metals (eg, zinc, iron, copper, etc.).
  • a solution of hydroxynaphthoic acid in a water-containing organic solvent is adsorbed through a weakly basic ion-exchange column and saturated.
  • ion exchange is performed through a solution of a physiologically active substance or a salt thereof in a water-containing organic solvent, and the solvent may be removed from the obtained effluent.
  • the organic solvent in the aqueous organic solvent alcohols (eg, methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, dimethylformamide and the like are used.
  • a method for removing the solvent for precipitating the salt a method known per se or a method analogous thereto is used. For example, there is a method of evaporating the solvent while adjusting the degree of vacuum using a rotary evaporator or the like.
  • Hydroxynaphthoate a physiologically active substance
  • the salt of the physiologically active peptide itself exerts a sustained release ability, so that the physiologically active substance is gradually released. And a sustained-release composition can be produced.
  • the product of the lactic acid-glycolic acid polymer used in the present invention is the product of the weight average molecular weight of the lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of the lactic acid-glycolic acid polymer. 2 0 0, 0 0 0 or more 3, 0 0 0, 0 0 or less, preferably 1, 500 0, 0 0 0 or more 2, 6 0 0, 0 0 0 or more Lactic acid-glycolic acid polymer below, and a lactic acid-glycolic acid polymer having a free hydroxyl group at a terminal is preferably used.
  • the lactic acid-glycolic acid polymer may be a salt.
  • the salt include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium), and organic bases (eg, organic amines such as triethylamine, basic amino acids such as arginine). And salts with transition metals (eg, zinc, iron, copper, etc.) and complex salts.
  • the composition ratio (mol%) of the lactic acid-glycolic acid polymer is preferably about 100/0 to about 40Z60, more preferably about 100Z0 to about 50Z50. Also, a lactic acid homopolymer having a composition ratio of 1000 is preferably used.
  • the optical isomer ratio of lactic acid which is one of the minimum repeating units of the “lactic acid-glycolic acid polymer” is preferably such that the D-form ZL-form (mol Z mol%) is in the range of about 75 25 to about 25Z75.
  • the D-form ZL-form (mol Z mol%) those having a range of about 60Z40 to about 30Z70 are generally used.
  • the weight average molecular weight of the “lactic acid-glycolic acid polymer” is usually about 3,000 to about 100,000, preferably about 3,000 to about 60,000, and more preferably about 3,000 to about 50,000. Particularly preferably, those having about 20,000 to about 50,000 are used.
  • the lactic acid-glycolic acid polymer of the present invention has a product of the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal carboxyl group amount (micromol) per unit mass (gram) of the lactic acid-glycolic acid polymer. It is from 1,200,000 to 3,000,000, and more preferably the weight average molecular weight of the lactic acid-glycolic acid polymer and the number of terminals per unit mass (gram) of the lactic acid-glycolic acid polymer.
  • the product of the amount of lipoxyl group (micromol) is 1,500,000 or more and 2,600,000 or less.
  • the dispersity (weight average molecular weight, Z number average molecular weight) is usually preferably about 1.2 to about 4.0, more preferably about 1.5 to 3.5, and particularly preferably about 1.7 to 3.0. Is preferred.
  • the amount of free carboxyl groups of the “lactic acid-glycolic acid polymer” is usually preferably about 20 to about 1000 iiiol (micromol) per unit mass (gram) of the polymer, and more preferably about 40 to about 1000 mol ( Micromolar) is particularly preferred.
  • micromol preferably about 40 to about 95 mol (micromol), more preferably about 50 to about 90 mol (micromol).
  • the weight average molecular weight is about 3,000 to about 100,000, and the weight average molecular weight of the lactate-dalicholic acid polymer and the terminal force per unit mass (dalam) of the lactate-dalicholate polymer A lactic acid-glycolic acid polymer having a product of the amount of lipoxyl group (micromol) of not less than 1,200,000 and not more than 3,000,000,
  • the weight-average molecular weight is about 3,000 to about 60,000, and the weight-average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal lipoxyl group per unit mass (gram) of lactic acid-dalicholic acid polymer Lactic acid-glycolic acid polymer having a product of (micromol) of not less than 1,200,000 and not more than 3,000,000,
  • the weight average molecular weight is about 3,000 to about 50,000, and the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal lipoxyl group amount per unit mass (gram) of the lactic acid-dalicholic acid polymer Lactic acid-glycolic acid polymer having a product of (micromol) of not less than 1,200,000 and not more than 3,000,000,
  • the weight average molecular weight is about 20,000 to about 50,000, and the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal carboxyl group per unit mass (dalum) of the lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a product of the amount (micromol) of not less than 1,200,000 and not more than 3,000,000,
  • the amount of terminal carboxyl group (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 to about 1000 ⁇ (micromol), and the weight average molecular weight of lactic acid-glycolic acid polymer Lactic acid-glycolic acid polymer having a product of terminal lipoxyl group amount (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer of not less than 1,200,000 and not more than 3,000,000,
  • Terminal carboxyl per unit mass (gram) of lactic acid-glycolic acid polymer The amount of silyl groups (micromoles) is about 40 to about 1000 ⁇ (micromoles), and the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal lipoxyl group per unit mass (grams) of the lactic acid-glycolic acid polymer Lactic acid-glycolic acid polymer whose product (amount of micromol) is not less than 1,200,000 and not more than 3,000,000, (7) 1 The weight average molecular weight is about 3,000 to about 100,000, 2 The amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is from about 20 to about 1000 mol (micromol), and 3 the weight average of lactate-dalicolic acid polymer A lactic acid-glycolic acid polymer having a product of a molecular weight and a terminal carboxyl group amount (micromol) per unit mass (gram) of the
  • the weight average molecular weight is about 3,000 to about 100,000
  • the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to about 1000 mol (micromol)
  • (3) the product of the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal lipoxyl group (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is 1 Lactic acid-glycolic acid polymer having a molecular weight of 200,000 or more and 3,000,000 or less
  • (9) 1 The weight average molecular weight is about 3,000 to about 60,000, 2
  • the amount of terminal lipoxyl groups (mole per mole) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 Approximately 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer
  • (10) 1 The weight-average molecular weight is about 3,000 to about 60,000, 2
  • the amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (mole mole) is about 40 to Approximately 1000 mol (micromol)
  • (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the amount (micromol) of terminal lipoxyl groups per unit mass (gram) of lactic acid-dalicholic acid polymer A lactic acid-glycolic acid polymer having a product of not less than 1,200,000 and not more than 3,000,000, (11) 1
  • the weight average molecular weight is about 3,000 to about 50,000, 2
  • the amount of terminal carboxyl groups per unit mass (gram) of mono-lactic acid-dalicholic acid (gram) is about 20%.
  • the weight-average molecular weight is about 3,000 to about 50,000
  • the amount of terminal carboxyl groups per unit mass (gram) of lactic acid-dalicholate polymer is about 40 to It is about 1 000 mol (micromol)
  • (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a product of not less than 1,200,000 and not more than 3,000,000,
  • the weight average molecular weight is about 20,000 to about 50,000
  • the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 to about 100000 / zmol (micromol)
  • 3 the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer Lactic acid-glycolic acid polymer having a product of not less than 1,200,000 and not more than 3,000,000, and
  • the weight-average molecular weight is about 20,000 to about 50,000
  • the terminal lipoxyl group amount (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 And about 3,000 zmol (micromol)
  • (3) the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal lipoxyl groups per unit mass (gram) of lactic acid-dalicholic acid polymer (micromoles) Lactic acid-glycolic acid polymer with a product of 1,200,000 or more and 3,000,000 or less is a preferable example.
  • the weight average molecular weight is about 3,000 to about 100,000
  • the weight average molecular weight is about 3,000 to about 60,000
  • the weight average molecular weight is about 3,000 to about 50,000
  • the weight average molecular weight of lactic acid-dalicholate polymer and the terminal carboxyl per unit mass (dalam) of lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a product of base amounts (micromoles) of not less than 1,500,000 and not more than 2,600,000,
  • the weight average molecular weight is about 20,000 to about 50,000
  • 2 The weight average molecular weight of lactic acid-glycolic acid polymer and the terminal weight per unit mass (gram) of lactic acid-daricholic acid polymer A lactic acid-glycolic acid polymer having a product of the amount of carboxyl groups (micromoles) of not less than 1,500,000 and not more than 2,600,000,
  • the amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to about 1000 zmol (micromol); 2 Lactic acid-dalicholate polymer Lactic acid-glycolic acid whose product is the weight-average molecular weight of the product and the amount of terminal lipoxyl groups (micromoles) per unit mass (gram) of lactic acid-dalicholic acid polymer is from 1,500,000 to 2,600,000 Polymer,
  • (21) 1 The weight average molecular weight is about 3,000 to about 100,000, 2
  • the amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (My Chromol) is about 20 to about 1000 iinol (micromol), and (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the unit mass of lactic acid-glycolic acid polymer
  • Lactic acid-glycolic acid polymer having a product of terminal carboxyl group amount (micromol) per (gram) of not less than 1,500,000 and not more than 2,600,000,
  • the weight average molecular weight is about 3,000 to about 100,000, 2
  • the amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to Approximately 1000 mol (micromol), and 3 weight average molecular weight of lactic acid-glycolic acid polymer and unit mass of lactic acid-glycolic acid polymer
  • Lactic acid-glycolic acid polymer having a product of terminal lipoxyl group amount (micromol) per (gram) of not less than 1,500,000 and not more than 2,600,000,
  • the weight average molecular weight is about 3,000 to about 60,000, and (2) The amount of terminal lipoxyl groups (mole per mole) per unit mass (gram) of lactate-dalicholate polymer is about 20. About 1000 mol (micromol), and (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer A lactic acid-glycolic acid polymer having a product of not less than 1,500,000 and not more than 2,600,000,
  • the weight average molecular weight is about 3,000 to about 60,000
  • the amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (Mike mouth mole) is about 40 to about 1000 mol (micromol)
  • (3) the product of the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is 1
  • the weight average molecular weight is about 3,000 to about 50,000, 2
  • the amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (mike mole) is about 20 to Approximately 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer
  • the weight-average molecular weight is about 3,000 to about 50,000, 2
  • the terminal lipoxyl group amount per unit mass (gram) of lactic acid-glycolic acid polymer (Mike mouth mole) is about 40.
  • the weight average molecular weight is about 20,000 to about 50,000
  • the terminal lipoxyl group amount (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 to It is about 1000 mol (micromol)
  • (3) the product of the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer is 1 Lactic acid-glycolic acid polymer having a molecular weight of 500,000 or more and 2,600,000 or less, and
  • the weight average molecular weight is about 20,000 to about 50,000
  • the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to about 1000 mol (micromol)
  • (3) the product of the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer is 1, Lactic acid-glycolic acid polymers having a molecular weight of 500,000 or more and 2,600,000 or less are exemplified.
  • the weight-average molecular weight, number-average molecular weight and dispersity in the present specification mean that the weight-average molecular weight is 1,110,000, 707,000, 455,645, 354,000, 189,000, 156,055, 98, Gel permeation mouth chromatography using fifteen monodisperse polystyrenes as reference materials: 900, 66, 437, 37, 200, 17, 100, 9, 830, 5, 870, 2,500, 1, 303, 504
  • the molecular weight in terms of polystyrene measured by (GPC) and the calculated degree of dispersion.
  • the measurement is performed using a high-speed GPC device (Tosoichi, HLC-8120GPC, detection method depends on the differential refractive index), GPC column KF804LX2 (Showa Denko), and chromatoform as the mobile phase.
  • Flow rate is lm 1 Zmin. La.
  • the amount of free carboxyl groups means a value obtained by a labeling method (hereinafter, referred to as “amount of carboxyl groups by labeling method”).
  • a labeling method hereinafter, referred to as “amount of carboxyl groups by labeling method”.
  • the “amount of lipoxyl group” is determined by dissolving a lactic acid-glycolic acid polymer in a mixed solvent of toluene-acetone / methanol, and titrating the carboxyl group with an alcoholic potassium hydroxide solution using phenolphthalein as an indicator. (Hereinafter, the value obtained by this method is referred to as “the amount of carboxyl group by the alkali titration method”).
  • the rate of decomposition and disappearance of the lactic acid-dalicholic acid polymer varies greatly depending on the copolymer composition, molecular weight and the amount of the free lipoxyl group, but in general, the lower the glycolic acid fraction, the slower the decomposition and disappearance.
  • the release period can be prolonged by lowering the fraction or increasing the molecular weight and reducing the amount of free lipoxyl groups.
  • the “lactic acid-glycolic acid polymer” is, for example, a non-catalytic dehydration polycondensation of lactic acid and glycolic acid (Japanese Patent Application Laid-Open No. 61-28521) or a catalyst derived from lactide and a cyclic diester compound such as glycolide.
  • the polymer obtained by the above-mentioned known ring-opening polymerization method does not necessarily have a free carboxyl group at the terminal of the obtained polymer.
  • EP-A-08399525 By subjecting the polymer to the hydrolysis reaction described in (1), the polymer can be modified into a polymer having a certain amount of carboxyl group per unit mass, and this can also be used.
  • lactic acid-glycolic acid polymer having a free carboxyl group at the terminal can be produced by a known production method (for example, a non-catalytic dehydration polycondensation method, see Japanese Patent Application Laid-Open No. 61-28521) without any problem. Alternatively, it can be produced by the following method.
  • a hydroxymonocarboxylic acid derivative having a protected carboxyl group eg, tert-butyl D-lactic acid, benzyl L-lactate
  • a hydroxydicarboxylic acid derivative having a protected carboxyl group eg, tartronic acid
  • the cyclic ester compound is subjected to a polymerization reaction using a polymerization catalyst in the presence of dibenzyl, ditert-butyl 2-hydroxymalonate, and the like.
  • hydroxylcarboxylic acid derivative having a protected carboxylic acid group or “hydroxydicarboxylic acid derivative having a protected carboxyl group” refers to, for example, a compound in which the carboxylic acid group (—CO OH) is an amide (1-C ⁇ NH) 2 ) Hydroxy carboxylic acid derivatives which are esterified or esterified (-COOR) are listed. Among them, the hydroxy group in which the carboxyl group (-COOH) is esterified (-COOR) is preferable. Carboxylic acid derivatives are preferred.
  • R in the ester e.g., methyl, Echiru, n- propyl, isopropyl, n- butyl, such as tert- butyl ( ⁇ - 6 alkyl group, for example, shea Kuropenchiru, C 3, such as cyclohexyl - 8 cycloalkyl groups such as phenylene Le, alpha-C 6 _ 1 2 7 aryl group such as naphthyl, for example, benzyl, such as phenethyl phenylene route C DOO 2 alkyl or alpha-naphthylmethyl etc. alpha-naphthyl One (: a 4- aralkyl group such as a 2- alkyl group, etc. Among them, a tert-butyl group, a benzyl group and the like are preferable.
  • cyclic ester compound refers to, for example, a cyclic compound having at least one ester bond in a ring. Specific examples include cyclic monoester compounds (lactones) and cyclic diester compounds (lactides).
  • cyclic monoester compound examples include 4-membered lactones (/ 3-propiolactone, 3-butyrolactone, / 3-isovalerolactone,) 3-force prolactone, _isoforce prolactone,) 3- Methyl-] 3-valerolactone, etc.), 5-membered lactones (such as aptyloractone, a-valerolactone), 6-membered lactones (such as ⁇ 5-valerolactone), and 7-membered lactones (such as ⁇ -force prolactone) , ⁇ -dioxanone, 1,5-dioxepan-2-one and the like.
  • cyclic diester compound examples include 4-membered lactones (/ 3-propiolactone, 3-butyrolactone, / 3-isovalerolactone,) 3-force prolactone, _isoforce prolactone,) 3- Methyl-] 3-valerolactone, etc.), 5-membered lactones (such as
  • R 'and R 2 are the same or different and each is a hydrogen atom or a methyl, Echiru, n-propyl, isopropyl, n- heptyl, showing a ⁇ alkyl group such as t one-butyl) compound represented by such as Of these, lactide in which R 1 is a hydrogen atom, R 2 is a methyl group, and R 1 and R 2 are each a hydrogen atom is preferred.
  • glycolide, L-lactide, D-lactide, DL-lactide, meso-lactide, 3-methyl-1,4-dioxane-2,5-dione (including optically active forms), etc. can give.
  • polymerization catalyst examples include organotin-based catalysts (eg, tin octylate, di-n-butyltin diphenylate, tetraphenyltin, etc.), aluminum-based catalysts (eg, triethylaluminum, etc.), zinc Based catalysts (eg, getyl zinc, etc.) '
  • organotin-based catalysts eg, tin octylate, di-n-butyltin diphenylate, tetraphenyltin, etc.
  • aluminum-based catalysts eg, triethylaluminum, etc.
  • zinc Based catalysts eg, getyl zinc, etc.
  • Aluminum-based catalysts and zinc-based catalysts are preferred from the viewpoint of ease of removal after the reaction, and zinc-based catalysts are more preferred from the viewpoint of safety when remaining.
  • benzene, hexane, toluene and the like are used, among which hexane and toluene are preferable.
  • the “polymerization method” refers to a bulk polymerization method in which the reactants are melted or a solution polymerization method in which the reactants are dissolved in an appropriate solvent (for example, benzene, toluene, xylene, decalin, dimethylformamide, etc.). It may be used. As the solvent, toluene, xylene and the like are preferable.
  • the polymerization temperature is not particularly limited.In the case of bulk polymerization, the temperature is not lower than the temperature at which the reactants are brought into a molten state at the start of the reaction, usually 100 to 300 ° C. When the reaction temperature is from room temperature to 150 ° C.
  • the reaction may be carried out by refluxing with a condenser or in a pressure vessel.
  • the polymerization time is appropriately determined in consideration of the polymerization temperature, other reaction conditions, physical properties of the target polymer, and the like, and is, for example, 10 minutes to 72 hours.
  • a suitable solvent eg, acetone, dichloromethane, chloroform, etc.
  • an acid eg, hydrochloric acid, acetic anhydride, trifluoroacetic acid, etc.
  • This is precipitated by mixing it in a solvent that does not dissolve the target substance (eg, alcohol, water, ether, isopropyl ether, etc.) according to a conventional method, and is precipitated by lactic acid-glycolic acid having a carboxyl group protected at the ⁇ -terminal.
  • the combination may be isolated.
  • the polymerization method of the present application is based on a hydroxycarboxylic acid derivative having a protected carboxyl group (eg, tert-butyl D-lactate, benzyl L-lactate) or a carboxyl group instead of a so-called protic chain transfer agent such as methanol.
  • a hydroxycarboxylic acid derivative having a protected group eg, dibenzyl tartronate, ditert-butyl 2-hydroxyethylmalonate
  • a hydroxydicarboxylic acid derivative having a protected group eg, dibenzyl tartronate, ditert-butyl 2-hydroxyethylmalonate
  • hydroxycarboxylic acid derivatives having a protected olepoxyl group eg, tert-butyl D-lactate, benzyl L-lactate
  • hydroxydicarboxylic acid derivatives having a protected propyloxyl group eg, dibenzyl tartronate, 2-hydroxy
  • 1 the molecular weight can be controlled by the charge composition
  • a carboxyl group can be liberated at the ⁇ -end.
  • the protecting group can be removed by a method known per se. As such a method, any method can be used as long as the protecting group can be removed without affecting the ester bond of the poly (hydroxycarboxylic acid). Methods such as reduction and acid decomposition are mentioned.
  • Examples of the reduction method include catalytic reduction using a catalyst (eg, palladium carbon, palladium black, platinum oxide, etc.), reduction with sodium in liquid ammonium, reduction with dithiothreitol, and the like.
  • a catalyst eg, palladium carbon, palladium black, platinum oxide, etc.
  • reduction with sodium in liquid ammonium reduction with dithiothreitol, and the like.
  • palladium carbon is added to a polymer dissolved in ethyl acetate, dichloromethane, chloroform, etc. Deprotection can be achieved by bubbling hydrogen for about 20 minutes to about 4 hours at room temperature with vigorous stirring.
  • the acid decomposition method includes, for example, an inorganic acid (eg, hydrogen fluoride, hydrogen bromide, hydrogen chloride, etc.) or an organic acid (eg, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.) or a mixture thereof. Acid decomposition and the like. If necessary, a cation scavenger (eg, anisol, phenol, thioanisole, etc.) may be appropriately added during acid decomposition.
  • an inorganic acid eg, hydrogen fluoride, hydrogen bromide, hydrogen chloride, etc.
  • an organic acid eg, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.
  • a cation scavenger eg, anisol, phenol, thioanisole, etc.
  • acid-decomposing a polymer having a carboxyl group protected by a tert-butyl group at the ⁇ -end specifically, adding an appropriate amount of trifluoroacetic acid to a solution of the polymer in dichloromethane, xylene, toluene, etc.
  • deprotection can be achieved by dissolving the polymer in trifluoroacetic acid and stirring for about 1 hour at room temperature.
  • the acid decomposition method may be carried out immediately after the polymerization reaction, in which case it can also serve as a polymerization termination reaction.
  • the lactic acid-glycolic acid polymer obtained by the above deprotection reaction is subjected to an acid hydrolysis reaction, whereby the weight average molecular weight, the number average molecular weight or the terminal
  • the amount of carboxyl groups can be adjusted according to the purpose. Specifically, it can be carried out, for example, by the method described in EP-A-0 839 525 25 or a method analogous thereto.
  • the lactic acid-dalicholic acid polymer obtained as described above can be used as a base for producing a sustained-release preparation.
  • a polymer having a free carboxyl group that is not specified at the terminal can be produced by a known production method (for example, see WO94 / 15587).
  • a lactate-glycolic acid polymer whose terminal is converted into a free lipoxyl group by a chemical treatment after ring-opening polymerization may be, for example, one commercially available from Boehringer Ingelheim KG or the like. Good.
  • the lactic acid-glycolic acid polymer may be a salt (as the salt of the lactic acid-glycolic acid polymer, for example, the above-mentioned salts, etc.).
  • an inorganic base eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, etc.
  • organic base eg, organic amines such as triethylamine, basic amino acids such as arginine, etc.
  • (B) Weak acid salts of the bases listed in (a) above (eg, acetates, glycolates) in a solution of the lactic acid-glycolic acid polymer having the above-mentioned carboxylic acid group in an organic solvent.
  • (C) dissolving the above-mentioned lactic acid-glycolic acid polymer having a lipoxyl group in an organic solvent Isolate lactic acid-glycolic acid polymer after mixing with a weak acid (eg, acetate, glycomonolate) or oxide of transition metal (eg, zinc, iron, copper, etc.) Method, and the like.
  • a weak acid eg, acetate, glycomonolate
  • transition metal eg, zinc, iron, copper, etc.
  • the weight ratio of the physiologically active substance in the composition of the present invention varies depending on the kind of the physiologically active substance, the desired pharmacological effect and the duration of the effect, and the like.
  • the physiologically active substance or its salt and hydroxynaphthoic acid or its salt In the case of a sustained-release composition containing a lactic acid-glycolic acid polymer or a salt thereof, the sum of the three is, for example, about 0.000 for a bioactive peptide or a salt thereof. From 1 to about 50% by weight, preferably from about 0.02 to about 40% by weight, more preferably from about 0.1 to 30% by weight, most preferably from about 12 to 24% by weight.
  • the amount is about 0.01 to 80% by weight, preferably about 0.1 to 50% by weight.
  • the weight ratio is the same even when a physiologically active substance, hydroxynaphthoate, is contained.
  • (A) and (B) (A) is usually about 5 to about 90% by weight, preferably about 10 to about 85% by weight, more preferably about 15 to about 80% by weight, Particularly preferred is about 30 to about 80% by weight.
  • hydroxynaphthoic acid or a salt thereof is about 1 Z2 to about 2 mol, about 3/4 to about 4 da3 mol, particularly preferably about 4/5, per mol of a physiologically active substance or a salt thereof. About 6 Z 5 mol.
  • the design of the composition of the present invention is based on the case where the bioactive substance is basic for a sustained-release composition containing a bioactive substance, hydroxynaphthoic acid, and a polymer of lactate-dalicholic acid. This will be described below.
  • a bioactive substance as a base and hydroxynaphthoic acid as an acid coexist in the composition, and when they are incorporated in the composition as a free form or a salt, the composition is produced.
  • dissociation equilibrium is established in the presence of water or in the presence of trace amounts of water.
  • the salt formed by the slightly water-soluble hydroxynaphthoic acid with the physiologically active substance is considered to be slightly water-soluble depending on the properties of the physiologically active substance.
  • Lean In order to produce a composition containing a high content of a basic physiologically active substance, it is desirable to protonate most of the physiologically active substance to form the above slightly water-soluble salt in view of the above dissociation equilibrium. For this purpose, it is desirable to mix hydroxynaphthoic acid or a salt thereof that is at least equivalent to a physiologically active substance or a salt thereof.
  • the counter ion is mainly hydroxynaphthoic acid.
  • the oligomers and monomers begin to form over time due to the degradation of the polymer of lactate-dalicholate, and the oligomers (lactate-dalicholate oligomer) and the monomers (lactate-lactic acid) are formed.
  • glycolic acid always has one carboxyl group, which can also be a counter ion of a physiologically active substance.
  • the release of a bioactive substance does not involve the transfer of charge, ie, the force performed as a salt with a counter ion.
  • a bioactive substance as described above, hydroxynaphthoic acid, lactate-dalicholate oligomer To a certain degree of molecular weight) and monomers (lactic acid or glycolic acid).
  • a salt of a strong acid generally occurs preferentially, depending on the composition ratio.
  • the pK a of hydroxynaphthoic acid is, for example, that of 3-hydroxy-2-naphthoic acid is 2.708 (Chemical Handbook Basic Edition II, The Chemical Society of Japan, issued September 25, 1969) .
  • the pKa of the carboxyl group of the lactic acid-glycolic acid oligomer is Considering the contribution of the closest ester bond
  • the salt formed by hydroxynaphthoic acid with the physiologically active substance is slightly water-soluble and not water-insoluble has a favorable effect on the sustained-release mechanism. That is, as clarified in the consideration of the acid dissociation constant, as a salt of a mobile physiologically active substance, in the early stage of release, a salt of hydroxynaphthoic acid, which is a stronger acid than the above-mentioned lactic acid-dalicholic acid oligomer and monomer, is used.
  • the solubility of the salt and the distribution to the body tissue are determinants of the release rate of the bioactive substance, so the amount of hydroxynaphthoic acid controls the initial release pattern of the drug.
  • water-insoluble as used herein means that when the substance is stirred in distilled water at a temperature of 40 ° C or lower for 4 hours, the mass of the substance dissolved in 1 L of the solution is 25 mg or lower. .
  • “slightly water-soluble” means that the mass is greater than 25 mg and 5 g or less. Refers to the case below.
  • the substance is a salt of a physiologically active substance
  • the above definition is applied with the mass of the physiologically active substance dissolved in the above operation.
  • the form of the sustained release composition in the present specification is not particularly limited, but is preferably in the form of fine particles, and particularly in the form of microspheres (in the case of a sustained release composition containing a lactic acid-glycolic acid polymer, also referred to as microcapsules). preferable.
  • the microsphere in this specification refers to injectable spherical fine particles that can be dispersed in a solution. The confirmation of the form can be performed, for example, by observation with a scanning electron microscope.
  • a sustained-release composition containing the physiologically active substance of the present invention or a salt thereof, hydroxynaphthoic acid or a salt thereof, and a lactic acid-glycolic acid polymer or a salt thereof, for example, a method for producing a microcapsule is exemplified. .
  • an organic solvent solution of hydroxynaphthoic acid or a salt thereof and a polymer of lactic acid-dalicholic acid or a salt thereof is prepared.
  • the organic solvent used for producing the sustained-release preparation of the present invention preferably has a boiling point of 120 ° C. or lower.
  • organic solvent examples include halogenated hydrocarbons (eg, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), fatty acid esters (eg, acetic acid) Examples thereof include ethyl, butyl acetate, etc., aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), and acetonitrile.
  • dichloromethane is particularly preferable.
  • organic solvent of hydroxynaphthoic acid or a salt thereof alcohols or a mixture of an alcohol and a halogenated hydrocarbon is preferable.
  • Hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof may be separately dissolved and then mixed, or these may be used by dissolving the two in an organic solvent mixed in an appropriate ratio. You may. Among them, halogenated carbon A mixed solution of hydrogen hydride and alcohol is preferred, and a mixed solution of dichloromethane and ethanol is particularly preferred.
  • the content of ethanol in the mixed organic solvent of dichloromethane and ethanol is generally about 0.01 to about 50% (v / v;). And more preferably from about 0.05 to about 40% (v / v), particularly preferably from about 0.1 to about 30% (v / v).
  • the concentration of the polymer of lactate-dalicholate in an organic solvent varies depending on the molecular weight of the lactate-dalicholate polymer and the type of organic solvent.For example, when dichloromethane is used as an organic solvent, it is generally about 0%. 5 to about 70% by weight, more preferably about 1 to about 60% by weight, particularly preferably about 2 to about 50% by weight.
  • the concentration of hydroxynaphthoic acid or a salt thereof in an organic solvent is generally about 0.01 to about 10% by weight, more preferably about 10% by weight, when a mixture of dichloromethane and ethanol is used as the organic solvent. 0.1 to about 5% by weight, particularly preferably about 0.5 to about 3% by weight.
  • a physiologically active substance or a salt thereof is added to the thus-obtained solution of hydroxynaphthoic acid or a salt thereof and the lactic acid-glycolic acid polymer in an organic solvent, and dissolved or dispersed.
  • an organic solvent solution containing the obtained composition comprising a physiologically active substance or a salt thereof, hydroxysinaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof is added to an aqueous phase, and ⁇ (oil phase) ZW ( (Aqueous phase)
  • the solvent in the oil phase is volatilized or diffused in the aqueous phase to prepare a microcapsule.
  • the volume of the aqueous phase at this time is generally about 1 to about 100,000 times the volume of the oil phase, more preferably about 5 to about 500,000 times, and particularly preferably about 1 to 100,000 times. It is selected from 0 times to about 2,000 times.
  • An emulsifier may be added to the above external water phase.
  • any emulsifier can be used as long as it can form a stable OZW emulsion.
  • anionic surfactants sodium oleate, sodium stearate, sodium lauryl sulfate, etc.
  • nonionic surfactants polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween 60, Atlas Powder —, Polyoxyethylene castor oil derivatives [HCO-60, HCO-50, Nikko Chemicals] etc.
  • polyvinylpyrrolidone polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid and the like.
  • concentration at the time of use is preferably in the range of about 0.001 to 10% by weight, more preferably in the range of about 0.001 to about 5% by weight.
  • An osmotic pressure regulator may be added to the above external aqueous phase.
  • the osmotic pressure adjusting agent may be any as long as it exhibits an osmotic pressure when used as an aqueous solution.
  • osmotic pressure adjusting agent examples include polyhydric alcohols, monohydric alcohols, monosaccharides, disaccharides, oligosaccharides, amino acids, and derivatives thereof.
  • polyhydric alcohols examples include trihydric alcohols such as glycerin, pentahydric alcohols such as arabiol, xylitol and aditol, and hexahydric alcohols such as mannitol, sorbitol and dulcitol. Can be Of these, hexahydric alcohols are preferred, and mannitol is particularly preferred.
  • Examples of the above monohydric alcohols include methanol, ethanol, isopropyl alcohol and the like, and among them, ethanol is preferable.
  • Examples of the above-mentioned monosaccharides include pentoses such as arabinose, xylose, ribose and 2-deoxyribose, and hexoses such as glucose, fructose, galactose, manose, sorbose, rhamnose and fucose. Hexasaccharides are preferred.
  • oligosaccharides for example, trisaccharides such as maltotriose and raffinose monosaccharide, tetrasaccharides such as stachyose and the like are used, among which trisaccharides are preferable.
  • disaccharides and oligosaccharides for example, dalcosamine, galactosamine, glucuronic acid, galacturonic acid and the like are used.
  • any L-form amino acid can be used, and examples thereof include glycine, leucine, arginine and the like. Of these, L-arginine is preferred. These osmotic pressure regulators may be used alone or as a mixture.
  • osmotic pressure adjusting agents are used at a concentration such that the osmotic pressure of the external aqueous phase is about 1 Z50 to about 5 times, preferably about 1 Z25 to about 3 times the osmotic pressure of physiological saline.
  • a method for removing the organic solvent a method known per se or a method analogous thereto is used. For example, a method of evaporating an organic solvent at normal pressure or gradually reducing pressure while stirring with a propeller type stirrer, a magnetic stirrer, an ultrasonic generator, or the like, or a method of reducing the degree of vacuum using a rotary evaporator, etc. There are a method of evaporating the organic solvent while adjusting, and a method of gradually removing the organic solvent using a dialysis membrane.
  • micro forcepsel obtained in this manner is separated by centrifugation or filtration, and then free bioactive substances or salts thereof, hydroxynaphthoic acid or salts thereof, drugs adhering to the surface of the microcapsules, drugs Wash the retentate, emulsifier, etc. several times with distilled water, disperse again in distilled water, etc., and freeze-dry.
  • an anti-agglomeration agent may be added to prevent aggregation of the particles.
  • the aggregation inhibitor include water-soluble polysaccharides such as mannitol, lactose, glucose, starches (eg, corn starch), amino acids such as glycine, and proteins such as fibrin and collagen. Of these, mannitol is preferred.
  • the water and the organic solvent in the microcapsules may be removed by heating under reduced pressure so that the microcapsules do not fuse together.
  • the mixture is heated at a temperature slightly higher than the midpoint glass transition temperature of the lactic acid-glycolic acid polymer determined by a differential scanning calorimeter under the condition of a heating rate of 10 to 20 ° C. per minute. More preferably, heating is performed within a temperature range about 30 degrees higher than the midpoint glass transition temperature of the lactic acid-glycolic acid polymer.
  • the temperature range is higher than the midpoint glass transition temperature of the lactic acid-glycolic acid polymer by 10 ° C higher than the midpoint glass transition temperature, and more preferably, higher than the midpoint glass transition temperature by 5 "C higher than the midpoint glass transition temperature. Heat in the temperature range.
  • the heating time varies depending on the amount of microcapsules, etc. After the black capsule itself reaches a predetermined temperature, about 12 hours to about 168 hours, preferably about 24 hours to about 120 hours, particularly preferably about 48 hours to about 96 hours It is.
  • the method of heating is not particularly limited as long as the method is capable of uniformly heating the aggregate of microcapsules.
  • the heating and drying method for example, a method of heating and drying in a constant temperature bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like are used. Of these, the method of heating and drying in a thermostat is preferred.
  • an organic solvent solution of a lactic acid-daricholic acid polymer or a salt thereof is prepared.
  • concentrations of the organic solvent and the lactic acid-dalicholic acid polymer or a salt thereof in the organic solvent solution are the same as those described in the above (I) ( ⁇ ).
  • the ratio between the two is the same as described in the above section (I) (i).
  • a physiologically active substance or a salt thereof is added to an organic solvent solution of the lactic acid-glycolic acid polymer or a salt thereof thus obtained and dissolved or dispersed.
  • a solution of hydroxynaphthoic acid or a salt thereof is added to an organic solvent solution (oil phase) containing a composition comprising the obtained physiologically active substance or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof (as the solvent).
  • This mixture is emulsified by a known method such as a homogenizer or ultrasonic waves to form a WZO emulsion.
  • a wzo emulsion comprising the obtained physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof is added to an aqueous phase, and w (internal aqueous phase) is added.
  • w internal aqueous phase
  • IW outer water phase
  • the volume of the external water phase is generally about 1 to about 100,000 times the oil phase volume, more preferably about 5 to about 5,000 times, particularly preferably about 10 to 100 times. It is selected from double to about 2000 times.
  • Emulsifiers and osmotic pressure regulators that may be added to the above external aqueous phase, and subsequent preparation methods Is the same as described in the above (I) (i).
  • an organic solvent solution of hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof is prepared, and the obtained organic solvent solution is referred to as an oil phase.
  • the preparation method is the same as described in the above (I) (i).
  • hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer may be separately prepared as organic solvent solutions, and then mixed.
  • the concentration of the lactic acid-glycolic acid polymer in the organic solvent solution varies depending on the molecular weight of the lactic acid-glycolic acid polymer and the type of the organic solvent.For example, when dichloromethane is used as the organic solvent, it is generally about 0.5 to 0.5%. It is selected from about 70% by weight, more preferably from about 1 to about 60% by weight, particularly preferably from about 2 to about 50% by weight.
  • a solution or dispersion of a physiologically active substance or a salt thereof is prepared (the solvent is water, a mixture of water and an alcohol (eg, methanol, ethanol, etc.)).
  • the concentration of the physiologically active substance or salt thereof is generally 0.001 mgZm 1 to 10 gZm, preferably 0.1 mgZm 1 to 5 g / m1, more preferably 1 Om / m1 to 3 gZm. Is one.
  • dissolution aids and stabilizers may be used.
  • heating, shaking, stirring and the like may be performed to such an extent that the activity is not lost, and the resulting aqueous solution is referred to as an internal aqueous phase.
  • the inner water phase and the oil phase obtained as described above are emulsified by a known method such as a homogenizer or ultrasonic waves to form a WZ emulsion.
  • the volume of the oil phase to be mixed is about 1 to about 1000 times, preferably about 2 to: L 00 times, more preferably about 3 to 10 times the volume of the internal aqueous phase.
  • the viscosity range of the obtained WZO emulsion is generally about 12-20, about 10-10,000 cp, preferably about 100-5, OOOcp.
  • the obtained biologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof, and a WZO emulsion composed of a lactic acid-glycolic acid polymer or a salt thereof are added to an aqueous phase, and w (internal aqueous phase) / O (Oil phase) IW (outer water phase) Form emulsion
  • the solvent in the oil phase is volatilized or diffused in the external water phase to prepare a microcapsule.
  • the volume of the external water phase is generally about 1 to about 100,000 times the oil phase volume, more preferably about 5 to about 500,000 times, and particularly preferably about 1 to 100,000 times. It is selected from 0 times to about 2,000 times.
  • the emulsifiers and osmotic pressure regulators that may be added to the above external aqueous phase, and the subsequent preparation method are the same as those described in the above (I) and (i).
  • the physiologically active substance or its salt, hydroxynaphthoic acid or its salt, and lactic acid-glycolic acid polymer or its salt described in the above-mentioned (I) in-water drying method can be used.
  • the coacervation agent is gradually added to the organic solvent solution containing the composition comprising the components under stirring to precipitate and solidify the mic-mouth gabcell.
  • the coacervation agent is selected from about 0.01 to 1.0 times, preferably about 0.05 to 500 times, particularly preferably about 0.1 to 200 times the oil phase volume. It is.
  • the coacervation agent may be a high molecular weight compound, a mineral oil type or a vegetable oil type compound or the like which is miscible with an organic solvent, such as a physiologically active substance or its salt, hydroxynaphthoic acid or its salt, and a lactic acid-glycolic acid polymer or There is no particular limitation as long as it does not dissolve the salt complex.
  • an organic solvent such as a physiologically active substance or its salt, hydroxynaphthoic acid or its salt, and a lactic acid-glycolic acid polymer or
  • silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like are used. These may be used as a mixture of two or more.
  • the micro forcepsel obtained in this way is collected, it is washed repeatedly with heptane or the like, and is washed with a physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or
  • the coacervation agent other than the salt composition is removed and dried under reduced pressure.
  • washing is carried out in the same manner as described in the above-mentioned (I) and (i) in-water drying method, followed by freeze-drying and further heating and drying.
  • microcapsules When microcapsules are produced by this method, the physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof described in the above (I) in-water drying method, and An organic solvent solution containing the lactic acid-glycolic acid polymer or a salt thereof is sprayed into the drying chamber of a spray drier using a nozzle, and the organic matter in the atomized droplets is discharged in a very short time. Evaporate the solvent to prepare microcapsules.
  • the nozzle include a two-fluid nozzle type, a pressure nozzle type, and a rotating disk type.
  • freeze drying and further heating drying may be performed. Adjust the degree of vacuum using an organic solvent solution containing a physiologically active substance or a salt thereof, a hydroxynaphthoic acid or a salt thereof, and a lactic acid-glycolic acid polymer or a salt thereof described in the underwater drying method, for example, using a rotary evaporator.
  • the organic solvent and water may be evaporated to dryness while drying, and then pulverized by a jet mill or the like to form fine powder (also referred to as microparticles).
  • the fine powder in the powder frame may be washed in the same manner as described in the underwater drying method of the microcapsule production method (I), and then freeze-dried, and further, may be heated and dried.
  • the microcapsules or fine powder obtained here can achieve drug release corresponding to the decomposition rate of the lactic acid-glycolic acid polymer used.
  • the sustained-release composition of the present invention may be in any form such as microspheres, microcapsules, and fine powder (microparticles), but microcapsules are preferred.
  • the sustained-release composition of the present invention can be formulated as it is or as a raw material into various dosage forms, and can be injected or implanted into intramuscular, subcutaneous, organs, etc., transmucosally into nasal cavity, rectum, uterus, etc.
  • oral preparations eg, capsules (eg, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, liquid preparations such as syrups, emulsions, suspensions, etc.
  • a dispersant eg, a surfactant such as Tween 80, HC0-60, sodium hyaluronate, carboxymethylcellulose, or alginic acid.
  • Polysaccharides such as sodium
  • preservatives eg, methylparaben, propylparaben, etc.
  • tonicity agents eg, sodium chloride, Aqueous suspension with mannitol, sorbitol, dextrose, proline, etc.
  • Disperses with vegetable oils such as sesame oil, corn oil, etc. to give sustained-release injections that can be used as oily suspensions. .
  • the particle size may be within a range that satisfies the dispersibility and the needle penetration property. ! 300 m, preferably in the range of about 0.5-150 im, more preferably in the range of about 1-100 m.
  • a method of sterilizing the whole production process a method of sterilizing with gamma ray, a method of adding a preservative, and the like are mentioned, but are not particularly limited.
  • the sustained-release composition of the present invention has low toxicity, it can be used as a drug safe for mammals (eg, humans, cows, pigs, dogs, cats, mice, rats, rabbits, etc.). it can.
  • the dosage of the sustained-release composition of the present invention varies depending on the type and content of the physiologically active substance as the main drug, the dosage form, the duration of release of the physiologically active substance, the target disease, the target animal, and the like. Any effective amount may be used.
  • the sustained-release preparation is a 6-month preparation
  • the dose of the physiologically active substance as the main drug is preferably in the range of about 0.01 mg to 1 OmgZkg body weight per adult. More preferably, it can be appropriately selected from the range of about 0.05 mg to 5 mgZkg body weight.
  • the dose of the sustained-release composition per dose is preferably selected from the range of about 0.05 mg to 5 OmgZkg, more preferably about 0.1 mg to 30 mgZ kg, per adult. Can be.
  • the frequency of administration is once every few weeks, once a month, or once every few months (eg, 3rd, 4th, 6th, etc.).
  • the sustained-release composition of the present invention can be used as a prophylactic / therapeutic agent for various diseases depending on the type of the physiologically active substance contained therein.
  • the physiologically active substance is an LH-RH derivative.
  • hormone-dependent diseases especially sex hormone-dependent cancers (Eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multi-ovarian ovary
  • sex hormone-dependent cancers Eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.
  • benign prostatic hyperplasia e.g, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multi-ovarian ovary
  • sex hormone-dependent cancers e.g, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.
  • benign prostatic hyperplasia e.g, endometriosis, uterine fibroids, precocious pubert
  • peptide A Acetate of 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 (hereinafter abbreviated as peptide A.
  • 1.2 g was dissolved in 1.2 ml of distilled water to obtain a DL-lactic acid polymer (weight average molecular weight of 40,600, number average molecular weight of 21,800, terminal carboxyl group of 52.7 z) (mol / g) 4.62 g and 0.18 g of 1-hydroxy-2-naphthoic acid were mixed with a solution of 8.25 ml of dichloromethane and 0.45 ml of ethanol in a mixed organic solvent.
  • the mixture was emulsified with a homogenizer to form a W / emulsion.
  • this WZO emulsion was injected into 1200 ml of a 0.1% (w / w) aqueous solution of polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry) which had been adjusted to 15 ° C in advance, and was then mixed with a turbine homomixer. And stirred at 7, OOOrpm to obtain WZOZW emulsion.
  • EG-40 polyvinyl alcohol
  • This WZOZW emulsion is stirred at room temperature for 3 hours to volatilize dichloromethane and ethanol or diffuse into the external water phase, solidify the oil phase, sieve through a sieve with openings of 75 111, and then centrifuge Using a separator (05PR-22, Hitachi, Ltd.), the microcapsules were settled and collected at 2,000 ⁇ ⁇ ⁇ for 5 minutes. This was dispersed again in distilled water, and further centrifuged to wash free drug and the like, and the microcapsules were collected. The collected microcapsules were redispersed by adding a small amount of distilled water, dissolved by adding 0.3 g of mannitol, and freeze-dried to obtain a powder. 46.91% mass recovery of microcapsules, peptide in microcapsules The A content was 18.7%, and the 1-hydroxy-2-naphthoic acid content was 2.57%.
  • a dispersing medium distilled water in which 0.15 mg of lipoxymethylcellulose, 0.3 mg of polysorbate 80, and 15 mg of mannitol were dissolved.
  • a dispersing medium distilled water in which 0.15 mg of lipoxymethylcellulose, 0.3 mg of polysorbate 80, and 15 mg of mannitol were dissolved.
  • Weekly male SD rats were injected subcutaneously into the back of the rat with a 22G needle. After a predetermined time from the administration, the rats were sacrificed and the microcapsules remaining at the administration site were taken out.
  • Peptide A in the microcapsules was quantified and divided by the initial content, and the survival rate obtained is shown in Table 1.
  • Example 2 6 weeks 12.63 ⁇ 4 15.63 ⁇ 4
  • Example 3 the microcapsules described in Example 1 manufactured by adding 1-hydroxy-2-naphthoic acid and the manufacturing performed by adding 3-hydroxy-2-naphthoic acid It can be seen that both the microcapsules described in Example 2 can contain a high amount of a physiologically active substance and have an effect of very well suppressing the initial excessive release of the physiologically active substance. These microcapsules have been able to release bioactive substances at a constant rate for a very long time.
  • Example 3 the microcapsules described in Example 1 manufactured by adding 1-hydroxy-2-naphthoic acid and the manufacturing performed by adding 3-hydroxy-2-naphthoic acid It can be seen that both the microcapsules described in Example 2 can contain a high amount of a physiologically active substance and have an effect of very well suppressing the initial excessive release of the physiologically active substance. These microcapsules have been able to release bioactive substances at a constant rate for a very long time.
  • Example 3 Approximately 250 mg of the microcapsules described in Example 3 was dispersed in 1.5 ml of a dispersing medium (0.75 mg of propyloxymethylcellulose, 1.5 mg of polysorbate 80, and distilled water in which 75 mg of mannitol was dissolved). Beagle dogs were dosed intramuscularly with a 22G needle. Further, about 125 mg of the microcapsules were dispersed in 0.75 ml of a dispersing medium (distilled water in which 0.375 mg of carboxymethylcellulose, 0.75 mg of polysorbate 80, and 37.5 mg of mannitol were dissolved), and the beagle dog It was administered subcutaneously to the gluteal area with a 22G injection needle. Blood is collected from the forearm vein at a predetermined time after administration, and serum B peptide B concentration (
  • DL-lactic acid polymer (weight average molecular weight 28,300, number average molecular weight 14,700, carboxyl group content 69.2 mo ⁇ / g by labeling assay) Mouth A solution prepared by dissolving 67 g of methane and 87.7 g of a solution of 9 g of 3-hydroxy-2-naphthoic acid in 210 g of dichloromethane and 16.2 g of ethanol was mixed. Adjusted to 8.
  • the mixture was injected in 5 minutes and 11 seconds, and stirred at 9, OOO rpm using H0M0MIC LINE FLOW (manufactured by Tokushu Kika) to form a W / OZW emulsion.
  • the temperature of the W / O / W emulsion was adjusted at 15 for 30 minutes, and then stirred for 2 hours and 30 minutes without temperature adjustment to evaporate dichloromethane and ethanol or diffuse them into the external aqueous phase to solidify the oil phase. Thereafter, the microcapsules were sieved using a sieve having an opening of 75111, and then the microcapsules were sedimented continuously at 2, OOO rpm using a centrifuge (H-600S, manufactured by Domestic Centrifuge) and collected.
  • H-600S manufactured by Domestic Centrifuge
  • the collected micro force peptide was redispersed in a small amount of distilled water, sieved using a 90-m mesh sieve, added with 12.3 g of mannitol, dissolved, and freeze-dried to obtain a powder.
  • the mass recovery of the microcapsule powder was 84.4 g and the recovery was 75.7%, the peptide A content was 17.8%, and the 3-hydroxy-2-naphthoic acid content was 2.5%. there were.
  • DL-lactic acid polymer (Weight average molecular weight 27,700, Number average molecular weight 15,700, Carboxyl group content by labeling assay 69.8 ⁇ mol / g) 107.8 g Dissolved in 83.9 g of dichloromethane Then, 7.5 g of 1-hydroxy- 12-naphthoic acid and 11.2 g of a solution of 175.8 g of dichloromethane and 13.5 g of ethanol were mixed to adjust the temperature to 28.2 ° C.
  • microcapsules were sieved using a sieve with a mesh opening, and then the microcapsules were continuously sedimented at 2, OOO rpm using a centrifuge (H-600S, manufactured by Domestic Centrifuge) and collected.
  • the collected microcapsules were re-dispersed in a small amount of distilled water, sieved using a sieve with a 90 / m mesh, added with 15.4 g of mannitol, dissolved, and freeze-dried to obtain a powder. Obtained.
  • the mass recovery of the microcapsule powder was 105.7 g with a recovery of 75.8%, the peptide A content was 18.4%, and the 1-hydroxy-2-naphthoic acid content was 2.8%. Met.
  • DL-lactic acid polymer (weight average molecular weight 30,800, number average molecular weight 13,900, amount of carboxyl group by labeling assay 66.3 / zmol / g)
  • a solution prepared by dissolving 83.3 g of dichloromethane in 7.5 g of 1-hydroxy-2-naphthoic acid was mixed with 19.7 g of a solution obtained by dissolving 7.5 g of dichloromethane and 13.5 g of ethanol. It was adjusted to 28.71. From this organic solvent solution, 274.3 g was weighed, and the peptide A acetate 24.898 was dissolved in 23.49 g of distilled water and heated to 51.2 ° C.
  • the resulting mixture was mixed with an aqueous solution, stirred for 5 minutes, coarsely emulsified, and then emulsified using a homogenizer under the conditions of 10,070 ⁇ ⁇ ⁇ for 5 minutes to form a W / O emulsion.
  • the WZO emulsion was cooled to 12.8 ° C, and then adjusted to 13.3 in advance in 25 liters of an aqueous (w / w) polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical) aqueous solution.
  • EG-40 polyvinyl alcohol
  • the mixture was injected in 4 minutes and 13 seconds, and stirred at 7, OOO rpm using HOMOMIC LINE FLOW (manufactured by Tokushu Kika) to form a WZO / W emulsion.
  • This W / OZW emulsion was temperature-adjusted at about 15 to 30 minutes, and then stirred for 2 hours and 30 minutes without temperature adjustment to allow dichloromethane and ethanol to evaporate or diffuse into the external aqueous phase to solidify the oil phase. After sieving, it is sieved using a 75 m sieve with an opening, and then centrifuged (H-600S, Microcapsules were sedimented continuously at 2, OOOrpm using a domestic centrifuge and collected.
  • H-600S Microcapsules were sedimented continuously at 2, OOOrpm using a domestic centrifuge and collected.
  • the collected microcapsules were redispersed in a small amount of distilled water, sieved using a sieve with a 90-m opening, added with 15.4 g of mannitol, dissolved, and freeze-dried to obtain a powder.
  • the mass recovery of the microcapsule powder was 101.9 g, the recovery was 73.1%, the peptide A content was 17.3%, and the 1-hydroxy-2-naphthoic acid content was 2. 9%.
  • microcapsules described in Examples 5 and 6 were dispersed in 0.3 ml of a dispersing medium (0.1 mg of rupoxymethylcellulose, 0.3 mg of polysorbate 80, and 15 mg of mannitol in distilled water).
  • a dispersing medium 0.1 mg of rupoxymethylcellulose, 0.3 mg of polysorbate 80, and 15 mg of mannitol in distilled water.
  • a 7-week-old male SD rat was subcutaneously administered to the back of the rat with a 22G needle.
  • the rats were sacrificed, and the microcapsules remaining at the administration site were taken out.
  • Peptide A in the microcapsules was quantified and divided by the initial content.
  • the sustained-release composition of the present invention contains a high content of a physiologically active substance, suppresses the initial excessive release, and can realize a stable release rate over a long period (preferably about 6 months or more).

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Abstract

Sustained release compositions containing a physiologically active substance or its salt, hydroxynaphthoic acid or its salt and a lactic acid-glycolic acid polymer or its salt, wherein the product of the weight-average molecular weight of the lactic acid-glycolic acid polymer by the amount (νmol) of the terminal carboxyl group per unit mass (g) of the lactic acid-glycolic acid polymer is from 1,200,000 to 3,000,000 (inclusive); and drugs, etc. containing these sustained release compositions.

Description

明 細 書 徐放性組成物、 その製造法および用途 技術分野  Description Sustained-release composition, its production method and application
本発明は、 生理活性物質の徐放性製剤およびその製造法に関する。  The present invention relates to a sustained-release preparation of a physiologically active substance and a method for producing the same.
背景技術 Background art
特開平 7— 97334号公報には、 生理活性ペプチドまたはその塩と末端に遊 離のカルボキシル基を有する生体内分解性ポリマーとからなる徐放性製剤およ びその製造法が開示されている。  JP-A-7-97334 discloses a sustained-release preparation comprising a physiologically active peptide or a salt thereof and a biodegradable polymer having a free carboxyl group at a terminal, and a method for producing the same.
GB2209937号、 GB2234169号、 GB2234896号、 GB 2257909号公報および EP 62617 OA 2号公報には、 別途調製したぺ プチド、 夕ンパク質のパモ酸塩等の水不溶性塩を含んでなる生体内分解性ポリマ —を基剤とした組成物またはその製造法が開示されている。  GB2209937, GB2234169, GB2234896, GB2257909 and EP 62617 OA2 disclose biodegradable polymers comprising separately prepared peptides and water-insoluble salts such as protein pamoate. -Based compositions or processes for their production are disclosed.
W〇95ノ15767号公報には、 cetrorelix (LH— RHアン夕ゴニスト） のェ ンボン酸塩 （パモ酸塩） およびその製造法が開示されていると同時に、 このパモ 酸塩を生体内分解性ポリマーに封入してもそのべプチドの放出性はパモ酸塩単 独での場合と同様であることが記述されている。 発明の開示  W-95 No. 15767 discloses embolic acid salt (pamoate) of cetrorelix (LH-RH angyu gonist) and a method for producing the same. It is described that the release of the peptide is similar to that of pamoate alone when encapsulated in a polymer. Disclosure of the invention
生理活性物質を高含量で含有し、 かつその初期過剰放出を抑制して長期にわた る （好ましくは約 6ヶ月以上） 安定した放出速度を実現できる新規組成物を提供 する。  Provided is a novel composition which contains a high content of a physiologically active substance and suppresses the initial excessive release, thereby realizing a stable release rate over a long period of time (preferably about 6 months or more).
本発明者らは、 上記の問題点を解決するために鋭意研究の結果、 組成物を形成 させる際に生理活性物質とヒドロキシナフトェ酸を共存させることにより生理 活性物質を高含量で組成物中に取り込み、 さらに乳酸ーグリコ一ル酸重合体中に 両者を封入した場合は、 乳酸一ダリコール酸重合体が存在しない条件下で調製し た生理活性物質とヒドロキシナフトェ酸から形成される組成物からの生理活性 物質の放出速度とは異なる速度で生理活性物質が放出され、 その放出速度が乳酸 ーグリコール酸重合体の特性ゃヒドロキシナフトェ酸の添加量によって制御可 能であり、 高含量においても確実に初期過剰放出を抑制して、 非常な長期にわた る （好ましくは約 6ヶ月以上） 持続放出を実現させることができ、 さらに該乳酸 ーグリコール酸重合体の重量平均分子量と該乳酸 -グリコール酸重合体の単位 質量 （グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） との積が 1， 200, 000以上 3, 000、 000以下である乳酸—グリコール酸重合体を 用いることにより、 より良い徐放性製剤を提供できることができることを見出し た。 さらに研究を重ねた結果、 本発明を完成するに至った。 The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a bioactive substance and a hydroxynaphthoic acid coexist when forming a composition, whereby the bioactive substance is contained in the composition at a high content. If both are encapsulated in the lactic acid-glycolic acid polymer, prepare it under the condition that the lactic acid-dalicholic acid polymer is not present. Bioactive substance is released at a rate different from the release rate of the bioactive substance from the composition formed from the bioactive substance and hydroxynaphthoic acid, and the release rate is the characteristic of lactic acid-glycolic acid polymer. It can be controlled by the amount of acid added, and can reliably suppress the initial excessive release even at a high content, and achieve a very long-term (preferably about 6 months or more) sustained release. The product of the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal lipoxyl group amount (micromol) per unit mass (gram) of the lactic acid-glycolic acid polymer is not less than 1,200,000 and 3,000,000 It has been found that a better sustained-release preparation can be provided by using the following lactic acid-glycolic acid polymer. As a result of further research, the present invention has been completed.
すなわち、 本発明は、  That is, the present invention
( 1)生理活性物質またはその塩、 ヒドロキシナフトェ酸またはその塩および乳酸 ーグリコール酸重合体またはその塩を含有し、 該乳酸ーグリコール酸重合体の重 量平均分子量と該乳酸一グリコール酸重合体の単位質量 （グラム） 当たりの末端 のカルボキシル基量 （マイクロモル） との積が 1， 200， 000以上 3, 00 0， 000以下である徐放性組成物、 (1) It contains a physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof, and the weight average molecular weight of the lactic acid-glycolic acid polymer and the A sustained-release composition having a product of terminal carboxyl group amount (micromol) per unit mass (gram) of not less than 1,200,000 and not more than 3,00000,
(2) 生理活性物質が生理活性ペプチドである上記 （1) 記載の徐放性組成物、 (2) The sustained-release composition according to the above (1), wherein the bioactive substance is a bioactive peptide,
(3) 生理活性物質が LH-RH誘導体である上記 （1) 記載の徐放性組成物、(3) The sustained-release composition according to the above (1), wherein the physiologically active substance is an LH-RH derivative,
(4) ヒドロキシナフトェ酸が 1—ヒドロキシ一 2—ナフトェ酸または 3—ヒド 口キシ— 2—ナフトェ酸である上記 （1) 記載の徐放性組成物、 (4) The sustained-release composition according to the above (1), wherein the hydroxynaphthoic acid is 1-hydroxy-12-naphthoic acid or 3-hydroxy-2-naphthoic acid.
(5)ヒドロキシナフトェ酸が 1 _ヒドロキシ— 2一ナフトェ酸である上記（1) 記載の徐放性組成物、  (5) The sustained-release composition according to the above (1), wherein the hydroxynaphthoic acid is 1-hydroxy-21-naphthoic acid,
(6) 乳酸—グリコール酸重合体の組成モル％が 100Z0〜40Z60である 上記 （1) 記載の徐放性組成物、  (6) The sustained release composition according to (1), wherein the composition mol% of the lactic acid-glycolic acid polymer is 100Z0 to 40Z60.
(7) 乳酸ーグリコール酸重合体の組成モル％が 100Z0である上記 （1) 記 載の徐放性組成物、  (7) The sustained release composition according to the above (1), wherein the composition mol% of the lactic acid-glycolic acid polymer is 100Z0,
( 8 )重合体の重量平均分子量が約 3, 000〜約 100， 000である上記（ 1 ) 記載の徐放性組成物、 (9) 重量平均分子量が約 20, 000〜 50， 000である上記 （8) 記載の 徐放性組成物、 (8) The sustained-release composition according to the above (1), wherein the polymer has a weight average molecular weight of about 3,000 to about 100,000. (9) The sustained-release composition according to the above (8), wherein the weight-average molecular weight is about 20,000 to 50,000,
(10) LH- RH誘導体が式  (10) LH-RH derivative has the formula
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
[式中、 Yは DLeu、 DAla、 DT卬、 DSer(tBu)、 D2Nalまたは DHis (ImBzl)を示し、 Zは H-C2H5または Gly- H2を示す。 ]で表されるペプチドである上記 （3) 記載の徐放 性組成物、 [Wherein, Y represents DLeu, DAla, DT 卬, DSer (tBu), D2Nal or DHis (ImBzl), and Z represents HC 2 H 5 or Gly-H 2 . ] The sustained release composition according to the above (3), which is a peptide represented by the formula:
(11) 重合体の末端の力ルポキシル基量が重合体の単位質量 （グラム） あたり 50〜 90マイク口モルである上記 （ 1 ) 記載の徐放性組成物、  (11) The sustained-release composition according to the above (1), wherein the amount of lipoxyl group at the terminal of the polymer is 50 to 90 micole moles per unit mass (gram) of the polymer,
(12) ヒドロキシナフトェ酸またはその塩と LH-RH誘導体またはその塩のモル 比が 3対 4ないし 4対 3である上記 （3) 記載の徐放性組成物、  (12) The sustained-release composition according to the above (3), wherein the molar ratio of hydroxynaphthoic acid or a salt thereof to an LH-RH derivative or a salt thereof is 3: 4 to 4: 3.
(13) 徐放性組成物中、 LH-RH誘導体またはその塩が 12 % (w/w)から 24 % (w/w)含有される上記 （3) 記載の徐放性組成物、  (13) The sustained release composition according to the above (3), wherein the LH-RH derivative or a salt thereof is contained in an amount of 12% (w / w) to 24% (w / w) in the sustained release composition,
(14) 生理活性物質またはその塩が微水溶性または水溶性である上記 （1) 記 載の徐放性組成物、  (14) The sustained-release composition according to the above (1), wherein the physiologically active substance or a salt thereof is slightly water-soluble or water-soluble.
(15) 注射用である上記 （1) 記載の徐放性組成物、  (15) The sustained-release composition according to the above (1), which is for injection,
(16) 生理活性物質またはその塩、 乳酸ーグリコール酸重合体またはその塩お よびヒドロキシナフトェ酸またはその塩の混合液から溶媒を除去することを特 徴とする上記 （1) 記載の徐放性組成物の製造法、  (16) The sustained-release property as described in (1) above, wherein the solvent is removed from a mixture of a physiologically active substance or a salt thereof, a lactic acid-glycolic acid polymer or a salt thereof, and hydroxynaphthoic acid or a salt thereof. A method for producing the composition,
(17) 乳酸—グリコール酸重合体またはその塩およびヒドロキシナフトェ酸ま たはその塩を含有する有機溶媒溶液に生理活性物質またはその塩を混合、 分散し、 次いで有機溶媒を除去することを特徴とする上記 （16) 記載の製造法、  (17) A physiologically active substance or a salt thereof is mixed and dispersed in an organic solvent solution containing a lactic acid-glycolic acid polymer or a salt thereof and hydroxynaphthoic acid or a salt thereof, and then the organic solvent is removed. The production method according to the above (16),
(18) 生理活性物質またはその塩が生理活性物質またはその塩を含有する水溶 液である上記 （16) 記載の製造法、  (18) The method according to (16), wherein the physiologically active substance or a salt thereof is an aqueous solution containing the physiologically active substance or a salt thereof.
(19) 生理活性物質の塩が遊離塩基または酸との塩である上記 （16) 記載の 製造法、  (19) The process according to (16), wherein the salt of the physiologically active substance is a salt with a free base or an acid.
(20) 上記 （1) 記載の徐放性組成物を含有してなる医薬、  (20) a medicament comprising the sustained-release composition according to the above (1),
(21) 上記 （3) 記載の徐放性組成物を含有してなる前立腺癌、 前立腺肥大症、 子宮内膜症、 子宮筋腫、 子宮線維腫、 思春期早発症、 月経困難症もしくは乳癌の 予防、 治療剤または避妊剤、 (21) Prostate cancer, prostatic hyperplasia comprising the sustained release composition according to (3) above, Prevention of endometriosis, uterine fibroids, uterine fibroids, precocious puberty, dysmenorrhea or breast cancer, treatment or contraceptive,
(22) 少なくとも約 6ヶ月以上にわたって生理活性物質またはその塩を放出す る上記 （1) 記載の徐放性組成物、 および  (22) The sustained-release composition according to (1), which releases a physiologically active substance or a salt thereof for at least about 6 months or more, and
(23) 生理活性物質またはその塩、 1 _ヒドロキシー 2—ナフトェ酸またはそ の塩および生体内分解性ポリマーまたはその塩を含有してなる徐放性組成物な どを提供する。  (23) A sustained-release composition comprising a physiologically active substance or a salt thereof, 1-hydroxy-2-naphthoic acid or a salt thereof, and a biodegradable polymer or a salt thereof.
さらに、 本発明は、  Further, the present invention provides
(24) 生理活性物質またはその塩を含む液を内水相とし、 乳酸ーグリコール酸 重合体およびヒドロキシナフトェ酸またはその塩を含む溶液を油相とする (24) A solution containing a physiologically active substance or a salt thereof is used as an internal aqueous phase, and a solution containing a lactic acid-glycolic acid polymer and hydroxynaphthoic acid or a salt thereof is used as an oil phase.
〇型乳化物を製造し、 次いで溶媒を除去することを特徴とする上記 （16) 記載 の徐放性組成物の製造法、 A method for producing a sustained-release composition according to the above (16), wherein a 〇-type emulsion is produced, and then the solvent is removed.
(25) ヒドロキシナフトェ酸またはその塩を含む液を内水相とし、 生理活性物 質またはその塩および乳酸ーグリコール酸重合体またはその塩を含む溶液を油 相とする WZO型乳化物を製造し、 次いで溶媒を除去することを特徴とする上記 (16) 記載の徐放性組成物の製造法、  (25) A WZO-type emulsion is prepared in which a liquid containing hydroxynaphthoic acid or a salt thereof is used as an internal aqueous phase, and a solution containing a physiologically active substance or a salt thereof and a solution containing a lactic acid-glycolic acid polymer or a salt thereof is used as an oil phase. The method for producing a sustained-release composition according to the above (16), wherein the solvent is then removed,
(26) 生理活性ペプチドまたはその塩およびヒドロキシナフトェ酸またはその 塩を混合、 溶解し、 次いで溶媒を除去することを特徴とする上記 （16) 記載の 徐放性組成物の製造法、 および  (26) The method for producing a sustained-release composition according to (16), wherein the physiologically active peptide or a salt thereof and hydroxynaphthoic acid or a salt thereof are mixed and dissolved, and then the solvent is removed, and
(27) 溶媒の除去法が水中乾燥法である上記 （24) 〜上記 （26) のいずれ かに記載の徐放性組成物の製造法などを提供する。 本発明で用いられる生理活性物質は、 薬理学的に有用なものであれば特に限定 を受けないが、 非ペプチド化合物でもペプチド化合物でもよい。 非ペプチド化合 物としては、 ァゴニスト、 アン夕ゴニスト、 酵素阻害作用を有する化合物などが あげられる。 また、 ペプチド化合物としては、 例えば、 生理活性ペプチドが好ま しく、 分子量約 300〜約 40， 000、 好ましくは約 400〜約 30, 000、 さらに好ましくは約 500〜約 20， 000の生理活性べプチドなどが好適であ る (27) The method for producing a sustained-release composition according to any one of the above (24) to (26), wherein the method for removing the solvent is a water drying method. The physiologically active substance used in the present invention is not particularly limited as long as it is pharmacologically useful, and may be a non-peptide compound or a peptide compound. Examples of the non-peptidic compound include agonist, angonist, and a compound having an enzyme inhibitory action. As the peptide compound, for example, a bioactive peptide is preferable, and a bioactive peptide having a molecular weight of about 300 to about 40,000, preferably about 400 to about 30,000, and more preferably about 500 to about 20,000 is used. Is preferred To
該生理活性ペプチドとしては、 例えば、 黄体形成ホルモン放出ホルモン （L H - RH) 、 インスリン、 ソマトスタチン、 成長ホルモン、 成長ホルモン放出ホル モン（GH— R H) 、 プロラクチン、 エリスロポイエチン、 副腎皮質ホルモン、 メラノサイト刺激ホルモン、 甲状腺ホルモン放出ホルモン、 甲状腺刺激ホルモン、 黄体形成ホルモン、 卵胞刺激ホルモン、 バソプレシン、 ォキシトシン、 カルシト ニン、 ガストリン、 セクレチン、 パンクレオザィミン、 コレシストキニン、 アン ジォテンシン、 ヒト胎盤ラクト一ゲン、 ヒト絨毛性ゴナドトロピン、 エンケファ リン、 エンドルフィン、 キヨウトルフィン、 タフトシン、 サイモポイエチン、 サ ィモシン、 サイモチムリン、 胸腺液性因子、 血中胸腺因子、 腫瘍壊死因子、 コロ ニー誘導因子、 モチリン、 ディノルフィン、 ボンべシン、 ニューロテンシン、 セ ルレイン、 ブラジキニン、 心房性ナトリウム排泄増加因子、 神経成長因子、 細胞 増殖因子、 神経栄養因子、 エンドセリン拮抗作用を有するペプチド類などおよび その誘導体、 さらにはこれらのフラグメントまたはフラグメントの誘導体などが 挙げられる。  Examples of the bioactive peptide include luteinizing hormone-releasing hormone (LH-RH), insulin, somatostatin, growth hormone, growth hormone-releasing hormone (GH-RH), prolactin, erythropoietin, corticosteroids, melanocyte stimulation. Hormones, thyroid hormone releasing hormone, thyroid stimulating hormone, luteinizing hormone, follicle stimulating hormone, vasopressin, oxitocin, calcitonin, gastrin, secretin, pancreozymine, cholecystokinin, angiotensin, human placental lactogen, human Chorionic gonadotropin, enkephalin, endorphin, kyotorphin, tuftsin, thymopoietin, thymosin, thymothymulin, thymic factor, blood thymic factor, tumor necrosis factor, colo -Inducible factors, motilin, dinorphin, bombesin, neurotensin, cellulin, bradykinin, atrial natriuretic factor, nerve growth factor, cell growth factor, neurotrophic factor, peptides having endothelin antagonism, etc. Derivatives, as well as fragments or derivatives of these fragments.
本発明で用いられる生理活性物質はそれ自身であっても、 薬理学的に許容され る塩であってもよい。  The physiologically active substance used in the present invention may be itself or a pharmacologically acceptable salt.
このような塩としては、 該生理活性物質がアミノ基等の塩基性基を有する場合、 無機酸 （無機の遊離酸とも称する） （例、 炭酸、 重炭酸、 塩酸、 硫酸、 硝酸、 ホ ゥ酸等） 、 有機酸 （有機の遊離酸とも称する） （例、 コハク酸、 酢酸、 プロピオ ン酸、 トリフルォロ酢酸等） などとの塩が挙げられる。  Examples of such salts include, when the physiologically active substance has a basic group such as an amino group, an inorganic acid (also referred to as an inorganic free acid) (eg, carbonic acid, bicarbonate, hydrochloric acid, sulfuric acid, nitric acid, nitric acid, boric acid) Etc.) and salts with organic acids (also referred to as organic free acids) (eg, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.).
生理活性物質が力ルポキシル基等の酸性基を有する場合、 無機塩基 （無機の遊 離塩基とも称する） （例、 ナトリウム、 カリウム等のアルカリ金属、 カルシウム、 マグネシウム等のアルカリ土類金属など） や有機塩基 （有機の遊離塩基とも称す る） （例、 トリェチルァミン等の有機アミン類、 アルギニン等の塩基性アミノ酸 類等） などとの塩が挙げられる。 また、 生理活性ペプチドは金属錯体化合物 （例、 銅錯体、 亜鉛錯体等） を形成していてもよい。  When the physiologically active substance has an acidic group such as a lipoxyl group, an inorganic base (also referred to as an inorganic free base) (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium) or an organic Bases (also referred to as organic free bases) (eg, organic amines such as triethylamine, basic amino acids such as arginine, etc.) and the like. Further, the physiologically active peptide may form a metal complex compound (eg, a copper complex, a zinc complex, etc.).
該生理活性ペプチドの好ましい例としては、 L H— R H誘導体であって、 ホル モン依存性疾患、 特に性ホルモン依存性癌 （例、 前立腺癌、 子宮癌、 乳癌、 下垂 体腫瘍など） 、 前立腺肥大症、 子宮内膜症、 子宮筋腫、 思春期早発症、 月経困難 症、 無月経症、 月経前症候群、 多房性卵巣症候群等の性ホルモン依存性の疾患お よび避妊（もしくは、その休薬後のリバウンド効果を利用した場合には、不妊症） に有効な LH— RH誘導体またはその塩が挙げられる。 さらに性ホルモン非依存 性であるが L H— R H感受性である良性または悪性腫瘍などに有効な L H— R H誘導体またはその塩も挙げられる。 Preferred examples of the physiologically active peptide include LH-RH derivatives, Mon-dependent diseases, especially sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, none LH-RH derivatives effective for menstrual disorders, premenstrual syndrome, multi-ovarian ovary syndrome, and other sex hormone-dependent diseases and contraception (or infertility if the rebound effect after drug withdrawal is used) Or a salt thereof. Furthermore, LH-RH derivatives or salts thereof that are effective for benign or malignant tumors that are sex hormone-independent but LH-RH sensitive are also included.
LH— RH誘導体またはその塩の具体例としては、 例えば、 トリートメント ウイズ GnRH アナログ：コントラバーシス アンド . パースペクティブ (Treatment with GnRH analogs： Controversies and perspectives) [ゾ リレテ ノン バブリツシング グループ （株） （The Parthenon Publishing Group Ltd. ) 発行 1996年] 、 特表平 3— 503165号公報、 特開平 3— 10 1695号、 同 7 - 97334号および同 8— 259460号公報などに記載されているぺプ チド類が挙げられる。  Specific examples of the LH-RH derivative or its salt include, for example, Treatment with GnRH analog: Contraversies and perspectives [The Zirrete Non-Bubbling Group Co., Ltd. (The Parthenon Publishing Group) 1996)], Japanese Patent Application Laid-Open No. 3-503165, Japanese Patent Application Laid-Open Nos. 3-101695, 7-97334 and 8-259460, and the like. .
LH— RH誘導体としては、 LH— RHァゴニストまたは LH— RHアン夕ゴ ニス卜が挙げられるが、 LH— RHアン夕ゴニストとしては、例えば、一般式〔 I〕 X-D2Nal-D4ClPhe-D3Pal-Ser-A-B-Leu-C-Pro-DAlaNH2 Examples of LH-RH derivatives include LH-RH agonists and LH-RH angelists. Examples of LH-RH antagonists include, for example, a compound represented by the general formula [I] X-D2Nal-D4ClPhe-D3Pal-Ser -AB-Leu-C-Pro-DAlaNH 2
〔式中、 Xは N(4H2- furoyUGlyまたは NAcを、 Aは NMeTyr、 Tyr、 Aph(Atz) , NMeAph(Atz)から選ばれる残基を、 Bは DLys(Nic)、 DCit、 DLys (AzaglyNic) , DLys(AzaglyFur), DhArg(Et2)、 DAph(Atz)およ U¾hCi から選ばれる残基を、 Cは Lys(Nisp), Argまたは hArg(Et2)をそれぞれ示す〕で表わされる生理活性ペプチド またはその塩などが用いられる。 (In the formula, X is N (4H2-furoyUGly or NAc, A is a residue selected from NMeTyr, Tyr, Aph (Atz), NMeAph (Atz), B is DLys (Nic), DCit, DLys (AzaglyNic) , DLys (AzaglyFur), DhArg (Et 2 ), a residue selected from DAph (Atz) and U¾hCi, and C represents Lys (Nisp), Arg or hArg (Et 2 ), respectively.) Or a salt thereof is used.
LH— RHァゴニストとしては、 例えば、 一般式 〔II〕  As an LH-RH agonist, for example, the general formula [II]
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
〔式中、 Yは DLeu、 DAla、 DT卬、 DSer(tBu)、 D2Nalおよび!) His (ImBzl)から選ば れる残基を、 Zは NH-C2H5または Gly-NH2¾それぞれ示す〕で表わされる生理活性べ プチドまたはその塩などが用いられる。 特に、 Yが DLeuで、 Zが H-C2H5であるべ プチド （即ち、 5- oxo-Pro- His- Trp- Ser-Tyr- DLeu-Leu- Arg-Pro- NH- C2H5で表され るペプチド） が好適である。 Wherein Y represents a residue selected from DLeu, DAla, DT 卬, DSer (tBu), D2Nal and!) His (ImBzl), and Z represents NH-C 2 H 5 or Gly-NH 2 ¾, respectively. A physiologically active peptide represented by or a salt thereof is used. In particular, Table Y in is DLeu, Z is at HC 2 H 5 is a base peptide (i.e., 5- oxo-Pro- His- Trp- Ser -Tyr- DLeu-Leu- Arg-Pro- NH- C 2 H 5 Is Are preferred.
これらのペプチドは、 前記文献あるいは公報記載の方法あるいはこれに準じる 方法で製造することができる。 本明細書中で使用される略号の意味は次のとおりである：  These peptides can be produced by the method described in the above-mentioned literature or gazette or a method analogous thereto. The meanings of the abbreviations used herein are as follows:
略号 名称  Abbreviation Name
N(4H2-furoyl)Gly N-テトラヒドロフロイルグリシン残基  N (4H2-furoyl) Gly N-tetrahydrofuroylglycine residue
NAc： N -ァセチル基 NAc: N-acetyl group
D2Nal ： D-3-(2-ナフチル） ァラニン残基 D2Nal: D-3- (2-naphthyl) alanine residue
D4ClP e： D- 3- (4-クロ口） フエ二ルァラニン残基 D4ClP e: D-3- (4-black mouth) phenylalanine residue
D3Pal： D - 3- (3-ピリジル） ァラニン残基 D3Pal: D-3- (3-pyridyl) alanine residue
NMeTyr： N-メチルチロシン残基 NMeTyr: N-methyltyrosine residue
Aph(Atz) ： N- [5'- (3， -ァミノ- ΓΗ- Γ, 2'，4'-トリァゾリル)]フエ二 ルァラニン残基 Aph (Atz): N- [5 '-(3, -amino-ΓΗ-Γ, 2', 4'-triazolyl)] phenylalanine residue
NMeAph (Atz) ： N-メチル - [5'- (3'-アミノ- ΓΗ - 2', 4'-トリァゾリ ル)]フエ二ルァラニン残基 NMeAph (Atz): N-methyl- [5 '-(3'-amino-ΓΗ- 2', 4'-triazolyl)] phenylalanine residue
DLys (Nic) ： D- (e- N-二コチノィル） リシン残基  DLys (Nic): D- (e-N-nicotinyl) lysine residue
Dcit： D-シトルリン残基 Dcit: D-citrulline residue
DLys (AzaglyNic) ： D- (ァザグリシルニコチノィル） リシン残基  DLys (AzaglyNic): D- (azaglycylnicotinol) lysine residue
DLys (AzaglyFur) ： D- (ァザダリシルフラニル） リシン残基 DLys (AzaglyFur): D- (azadarisilfuranyl) lysine residue
DhArg(Et2) ： D-(N， Ν'-ジェチル）ホモアルギニン残基 DhArg (Et 2 ): D- (N, Ν'-Jetyl) homoarginine residue
DAph (Atz) ： D- Ν- [5'- (3'-ァミノ- ΓΗ - 2', 4'-トリァゾリル)]フエ 二ルァラニン残基 DAph (Atz): D-Ν- [5 '-(3'-amino-ΓΗ-2', 4'-triazolyl)] pheniralanine residue
DhCi： D -ホモシトルリン残基 DhCi: D-homocitrulline residue
Lys (Nisp) ： (e- Ν-ィソプ口ピル） リシン残基 Lys (Nisp): (e-Ν-isop mouth pill) Lysine residue
hArg(Et2) ： (N, N' -ジェチル）ホモアルギニン残基 hArg (Et 2 ): (N, N'-Jetyl) homoarginine residue
DSer(tBu) ： O-tert-ブチル— D—セリン DSer (tBu): O-tert-butyl-D-serine
DHis(ImBzl) ： 一 D—ヒスチジン その他アミノ酸に関し、略号で表示する場合、 IUPAC-IUBコミッション'ォブ' ノヾィオケミカ レ ' ノ一メンクレーチユア一 (Commission on Biochemical Nomenclature) (ョ一口ビアン 'ジャーナル'ォブ'バイオケミストリー（European Journal of Biochemistry)第 138巻、 9〜37頁 （1984年） ） による略号または 該当分野における慣用略号に基づくものとし、 また、 アミノ酸に関して光学異性 体がありうる場合は、 特に明示しなければ L体を示すものとする。 DHis (ImBzl): One D—Histidine For other amino acids, when indicated by abbreviations, IUPAC-IUB Commission 'Ob' Noiochemikare 'Commission on Biochemical Nomenclature' (European Journal of Biochemistry) Vol. 138, pp. 9-37 (1984)) or abbreviations commonly used in the relevant field. When amino acids may have optical isomers, L-forms shall be indicated unless otherwise specified. I do.
本発明に用いられるヒドロキシナフトェ酸は、 ナフタレンの異なる炭素に 1つ の水酸基と 1つの力ルポキシル基が結合したものである。 従って、 カルボキシル 基の位置がナフ夕レン環の 1位と 2位であるそれぞれに対して水酸基の位置が 異なる合計 14種の異性体が存在する。 そしてこの中の任意の異性体を用いてよ く、 またこれらの任意の割合の混合物を用いてもよい。 後述するが、 酸解離定数 の大きなものが好ましく、 あるいは pKa (pKa = - 1 o 1 OKa, Kaは 酸解離定数を表す） の小さいものが好ましい。 そして微水溶性のものが好ましい。 また、 アルコール類 （例えば、 エタノール、 メタノール等） に可溶であるもの が好ましい。 「アルコール類に可溶」 とは例えばメタノールに対して 10 gZL 以上であることを意味する。  The hydroxynaphthoic acid used in the present invention is one in which one hydroxyl group and one hydroxyl group are bonded to different carbons of naphthalene. Therefore, there are a total of 14 isomers that differ in the position of the hydroxyl group from the positions 1 and 2 of the carboxyl group in the naphthylene ring. Any of these isomers may be used, and a mixture of these in any ratio may be used. As will be described later, those having a large acid dissociation constant are preferable, or those having a small pKa (pKa = -1 o1 OKa, Ka represents an acid dissociation constant) are preferable. And a slightly water-soluble one is preferred. Further, those soluble in alcohols (eg, ethanol, methanol, etc.) are preferable. “Soluble in alcohols” means, for example, 10 gZL or more with respect to methanol.
上記のヒドロキシナフトェ酸異性体の p K aとしては、 3—ヒドロキシ— 2— ナフトェ酸の値 （ pKa==2. 708、 化学便覧 基礎編 I I、 日本化学会、 昭和 44年 9月 25日発行） のみが知られているが、 ヒドロキシ安息香酸の 3種 の異性体の p K aを比較することによって有用な知見が得られる。 すなわち m— ヒドロキシ安息香酸と p—ヒドロキシ安息香酸の p K aが 4以上であるのに対 して o—ヒドロキシ安息香酸 （サリチル酸） の pKa (=2. 754) は極端に 小さい。 従って、 上記 14種の異性体のなかでも、 ナフ夕レン環の隣接する炭素 原子に力ルポキシル基と水酸基が結合した、 3—ヒドロキシー 2—ナフトェ酸、 1—ヒドロキシ— 2—ナフトェ酸および 2—ヒドロキシ— 1—ナフトェ酸が好 ましい。  The pKa of the above hydroxynaphthoic acid isomer is the value of 3-hydroxy-2-naphthoic acid (pKa == 2.708, Handbook of Chemistry, Basic II, The Chemical Society of Japan, September 25, 1969. Published), but a useful finding can be obtained by comparing the pKa of the three isomers of hydroxybenzoic acid. That is, while the pKa of m-hydroxybenzoic acid and p-hydroxybenzoic acid is 4 or more, the pKa (= 2.754) of o-hydroxybenzoic acid (salicylic acid) is extremely small. Therefore, among the above 14 isomers, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid and 2-hydroxy-2-naphthoic acid in which a carbonyl group and a hydroxyl group are bonded to adjacent carbon atoms of the naphthylene ring Hydroxy-1-naphthoic acid is preferred.
ヒドロキシナフトェ酸は塩であってもよい。塩としては、例えば、無機塩基（例、 ナトリウム、 カリウム等のアルカリ金属、 カルシウム、 マグネシウム等のアル力 リ土類金属など） や有機塩基 （例、 トリェチルァミン等の有機アミン類、 アルギ ニン等の塩基性アミノ酸類等） などとの塩、 または遷移金属 （例， 亜鉛， 鉄， 銅 など） との塩および錯塩などが挙げられる。 Hydroxynaphthoic acid may be a salt. Salts include, for example, inorganic bases (eg, Salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, etc.) and organic bases (eg, organic amines such as triethylamine, basic amino acids such as arginine), or Examples include salts and complex salts with transition metals (eg, zinc, iron, copper, etc.).
以下に、 本発明の生理活性物質のヒドロキシナフトェ酸塩の調製方法を例示す る。  Hereinafter, a method for preparing the hydroxynaphthoate of the physiologically active substance of the present invention will be described by way of example.
( 1 ) ヒドロキシナフトェ酸の含水有機溶媒溶液を弱塩基性イオン交換カラムに 通して吸着させ、 そして飽和させる。 次いで含水有機溶媒を通して過剰のヒドロ キシナフトェ酸を除去した後に生理活性物質またはその塩の含水有機溶媒溶液 を通してイオン交換を行わせて、 得られた流出液から溶媒を除去すればよい。 該 含水有機溶媒中の有機溶媒としては、 アルコール類 （例、 メタノール、 ェタノ一 ル等） 、 ァセトニトリル、 テトラヒドロフラン、 ジメチルホルムアミドなどが用 いられる。 塩を析出させるための溶媒を除去する方法は、 自体公知の方法あるい はそれに準じる方法が用いられる。 例えば、 ロータリーェヴアポレーターなどを 用いて真空度を調節しながら溶媒を蒸発させる方法などが挙げられる。  (1) A solution of hydroxynaphthoic acid in a water-containing organic solvent is adsorbed through a weakly basic ion-exchange column and saturated. Next, after removing excess hydroxynaphthoic acid through a water-containing organic solvent, ion exchange is performed through a solution of a physiologically active substance or a salt thereof in a water-containing organic solvent, and the solvent may be removed from the obtained effluent. As the organic solvent in the aqueous organic solvent, alcohols (eg, methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, dimethylformamide and the like are used. As a method for removing the solvent for precipitating the salt, a method known per se or a method analogous thereto is used. For example, there is a method of evaporating the solvent while adjusting the degree of vacuum using a rotary evaporator or the like.
( 2 ) 予め、 強塩基性イオン交換カラムの交換イオンを水酸化物イオンに交換し ておき、 これに生理活性物質またはその塩の含水有機溶媒溶液を通してそれらの 塩基性基を水酸化型に換える。 回収した流出液に当量以下のヒドロキシナフトェ 酸を加えて溶解し、 次いで濃縮して析出した塩を、 必要な場合には水洗して、 乾 燥すればよい。  (2) Exchange the exchange ions of the strong basic ion exchange column with hydroxide ions in advance, and convert the basic groups to hydroxylated form by passing a physiologically active substance or a salt thereof in a water-containing organic solvent solution. . The collected effluent may be dissolved by adding an equivalent or less of hydroxynaphthoic acid, and then the salt precipitated by concentration may be washed with water, if necessary, and dried.
生理活性物質のヒドロキシナフトェ酸塩は、 用いる生理活性物質にもよるが、 微水溶性であるため、 特に生理活性べプチドの該塩自身が徐放能を発揮して生理 活性物質の徐放性製剤に用いることができるし、 また、 さらに徐放性組成物を製 造することもできる。  Hydroxynaphthoate, a physiologically active substance, is slightly water-soluble, although it depends on the physiologically active substance used. In particular, the salt of the physiologically active peptide itself exerts a sustained release ability, so that the physiologically active substance is gradually released. And a sustained-release composition can be produced.
本発明に用いられる乳酸ーグリコール酸重合体は該乳酸ーグリコール酸重合 体の重量平均分子量と該乳酸ーグリコール酸重合体の単位質量 （グラム） 当たり の末端のカルボキシル基量 （マイクロモル） の積が 1， 2 0 0 , 0 0 0以上 3， 0 0 0 , 0 0 0以下、 好ましくは 1 , 5 0 0 , 0 0 0以上 2， 6 0 0， 0 0 0以 下である乳酸ーグリコ一ル酸重合体であり、 末端に遊離の力ルポキシル基を有す る乳酸ーグリコール酸重合体が好ましく用いられる。 The product of the lactic acid-glycolic acid polymer used in the present invention is the product of the weight average molecular weight of the lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of the lactic acid-glycolic acid polymer. 2 0 0, 0 0 0 or more 3, 0 0 0, 0 0 0 or less, preferably 1, 500 0, 0 0 0 or more 2, 6 0 0, 0 0 0 or more Lactic acid-glycolic acid polymer below, and a lactic acid-glycolic acid polymer having a free hydroxyl group at a terminal is preferably used.
乳酸ーグリコール酸重合体は塩であってもよい。 塩としては、 例えば、 無機塩 基 （例、 ナトリウム、 カリウム等のアルカリ金属、 カルシウム、 マグネシウム等 のアルカリ土類金属など） や有機塩基 （例、 トリェチルァミン等の有機アミン類、 アルギニン等の塩基性アミノ酸類等） などとの塩、 または遷移金属 （例， 亜鉛， 鉄， 銅など） との塩および錯塩などが挙げられる。  The lactic acid-glycolic acid polymer may be a salt. Examples of the salt include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium), and organic bases (eg, organic amines such as triethylamine, basic amino acids such as arginine). And salts with transition metals (eg, zinc, iron, copper, etc.) and complex salts.
また、 該乳酸一グリコール酸重合体の組成比 （モル％) は約 100/0〜約 4 0Z60が好ましく、 約 100Z0〜約 50Z50がより好ましい。 また、 組成 比が 100 0である乳酸ホモポリマーも好ましく用いられる。  The composition ratio (mol%) of the lactic acid-glycolic acid polymer is preferably about 100/0 to about 40Z60, more preferably about 100Z0 to about 50Z50. Also, a lactic acid homopolymer having a composition ratio of 1000 is preferably used.
該 「乳酸ーグリコール酸重合体」 の最小繰り返し単位の一つである乳酸の光学 異性体比は、 D—体 ZL—体 （モル Zモル％) が約 75 25〜約 25Z75の 範囲のものが好ましい。 この D—体 ZL—体 （モル Zモル％) は、 特に約 60Z 40〜約 30Z70の範囲のものが汎用される。  The optical isomer ratio of lactic acid, which is one of the minimum repeating units of the “lactic acid-glycolic acid polymer”, is preferably such that the D-form ZL-form (mol Z mol%) is in the range of about 75 25 to about 25Z75. . As the D-form ZL-form (mol Z mol%), those having a range of about 60Z40 to about 30Z70 are generally used.
該 「乳酸ーグリコール酸重合体」 の重量平均分子量は、 通常、 約 3, 000〜 約 100, 000、 好ましくは約 3， 000〜約 60， 000、 さらに好ましく は約 3, 000〜約 50， 000、 特に好ましくは約 20， 000〜約 50， 0 00のものが用いられる。  The weight average molecular weight of the “lactic acid-glycolic acid polymer” is usually about 3,000 to about 100,000, preferably about 3,000 to about 60,000, and more preferably about 3,000 to about 50,000. Particularly preferably, those having about 20,000 to about 50,000 are used.
また、 本発明の乳酸ーグリコール酸重合体は、 該乳酸ーグリコール酸重合体の 重量平均分子量と該乳酸ーグリコール酸重合体の単位質量 （グラム） 当たりの末 端のカルボキシル基量 （マイクロモル） の積が 1， 200， 000以上 3， 00 0, 000以下であるが、 さらに好ましくは、 該乳酸ーグリコール酸重合体の重 量平均分子量と該乳酸一グリコール酸重合体の単位質量 （グラム） 当たりの末端 の力ルポキシル基量 （マイクロモル） の積が 1， 500， 000以上 2， 600, 000以下のものなどがあげられる。  In addition, the lactic acid-glycolic acid polymer of the present invention has a product of the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal carboxyl group amount (micromol) per unit mass (gram) of the lactic acid-glycolic acid polymer. It is from 1,200,000 to 3,000,000, and more preferably the weight average molecular weight of the lactic acid-glycolic acid polymer and the number of terminals per unit mass (gram) of the lactic acid-glycolic acid polymer. The product of the amount of lipoxyl group (micromol) is 1,500,000 or more and 2,600,000 or less.
また、 分散度 （重量平均分子量 Z数平均分子量） は、 通常約 1. 2〜約 4. 0 が好ましく、 さらには約 1. 5〜3. 5が好ましく、 特に約 1. 7〜3. 0が好 ましい。 該 「乳酸ーグリコール酸重合体」 の遊離のカルボキシル基量は、 重合体の単位 質量 （グラム） あたり通常約 20〜約 1000 iiiol (マイクロモル） が好まし く、 さらには約 40〜約 1000 mol (マイクロモル） が特に好ましい。 The dispersity (weight average molecular weight, Z number average molecular weight) is usually preferably about 1.2 to about 4.0, more preferably about 1.5 to 3.5, and particularly preferably about 1.7 to 3.0. Is preferred. The amount of free carboxyl groups of the “lactic acid-glycolic acid polymer” is usually preferably about 20 to about 1000 iiiol (micromol) per unit mass (gram) of the polymer, and more preferably about 40 to about 1000 mol ( Micromolar) is particularly preferred.
さらに、 好ましくは約 40〜約 95 mo 1 (マイクロモル） 、 より好ましくは 約 50〜約 90 mo l (マイクロモル） である。 Further, it is preferably about 40 to about 95 mol (micromol), more preferably about 50 to about 90 mol (micromol).
さらに、  Furthermore,
(1) 重量平均分子量が約 3, 000〜約 100， 000であり、 乳酸一ダリコ ール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 （ダラ ム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 200， 00 0以上 3， 000， 000以下である乳酸—グリコール酸重合体、  (1) The weight average molecular weight is about 3,000 to about 100,000, and the weight average molecular weight of the lactate-dalicholic acid polymer and the terminal force per unit mass (dalam) of the lactate-dalicholate polymer A lactic acid-glycolic acid polymer having a product of the amount of lipoxyl group (micromol) of not less than 1,200,000 and not more than 3,000,000,
(2) 重量平均分子量が約 3 , 000〜約 60， 000であり、 乳酸ーグリコー ル酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1, 200， 000以 上 3， 000， 000以下である乳酸ーグリコール酸重合体、  (2) The weight-average molecular weight is about 3,000 to about 60,000, and the weight-average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal lipoxyl group per unit mass (gram) of lactic acid-dalicholic acid polymer Lactic acid-glycolic acid polymer having a product of (micromol) of not less than 1,200,000 and not more than 3,000,000,
(3) 重量平均分子量が約 3， 000〜約 50， 000であり、 乳酸ーグリコー ル酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 200， 000以 上 3， 000， 000以下である乳酸ーグリコール酸重合体、 (3) The weight average molecular weight is about 3,000 to about 50,000, and the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal lipoxyl group amount per unit mass (gram) of the lactic acid-dalicholic acid polymer Lactic acid-glycolic acid polymer having a product of (micromol) of not less than 1,200,000 and not more than 3,000,000,
(4) 重量平均分子量が約 20， 000〜約 50， 000であり、 乳酸—グリコ ール酸重合体の重量平均分子量と乳酸ーグリコール酸重合体の単位質量 （ダラ ム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 200， 00 0以上 3, 000, 000以下である乳酸ーグリコール酸重合体、  (4) The weight average molecular weight is about 20,000 to about 50,000, and the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal carboxyl group per unit mass (dalum) of the lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a product of the amount (micromol) of not less than 1,200,000 and not more than 3,000,000,
(5) 乳酸ーグリコール酸重合体の単位質量 （グラム） 当たりの末端のカルポキ シル基量 （マイクロモル） が約 20〜約 1000 μιηοΐ (マイクロモル） であり、 乳酸 -グリコール酸重合体の重量平均分子量と乳酸一グリコール酸重合体の単 位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 200, 000以上 3， 000, 000以下である乳酸—グリコール酸重合体、 (5) The amount of terminal carboxyl group (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 to about 1000 μιηοΐ (micromol), and the weight average molecular weight of lactic acid-glycolic acid polymer Lactic acid-glycolic acid polymer having a product of terminal lipoxyl group amount (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer of not less than 1,200,000 and not more than 3,000,000,
(6) 乳酸ーグリコール酸重合体の単位質量 （グラム） 当たりの末端のカルボキ シル基量 （マイクロモル） が約 40〜約 1000 μπιοΐ (マイクロモル） であり、 乳酸ーグリコール酸重合体の重量平均分子量と乳酸ーグリコール酸重合体の単 位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 200, 000以上 3， 000， 000以下である乳酸—グリコール酸重合体、 (7) ①重量平均分子量が約 3， 000〜約 100, 000であり、 ②乳酸—グ リコール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイ クロモル） が約 20〜約 1000 mol (マイクロモル） であり、 かつ③乳酸一 ダリコール酸重合体の重量平均分子量と乳酸 -グリコール酸重合体の単位質量 (グラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 200, 000以上 3， 000， 000以下である乳酸ーグリコール酸重合体、 (6) Terminal carboxyl per unit mass (gram) of lactic acid-glycolic acid polymer The amount of silyl groups (micromoles) is about 40 to about 1000 μπιοΐ (micromoles), and the weight average molecular weight of the lactic acid-glycolic acid polymer and the terminal lipoxyl group per unit mass (grams) of the lactic acid-glycolic acid polymer Lactic acid-glycolic acid polymer whose product (amount of micromol) is not less than 1,200,000 and not more than 3,000,000, (7) ① The weight average molecular weight is about 3,000 to about 100,000, ② The amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is from about 20 to about 1000 mol (micromol), and ③ the weight average of lactate-dalicolic acid polymer A lactic acid-glycolic acid polymer having a product of a molecular weight and a terminal carboxyl group amount (micromol) per unit mass (gram) of the lactic acid-glycolic acid polymer of not less than 1,200,000 and not more than 3,000,000,
(8) ①重量平均分子量が約 3, 000〜約 100, 000であり、 ②乳酸ーグ リコール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイ クロモル） が約 40〜約 1000 mol (マイクロモル） であり、 かつ③乳酸— ダリコール酸重合体の重量平均分子量と乳酸 -グリコール酸重合体の単位質量 (グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1, 200， 000以上 3， 000, 000以下である乳酸—グリコール酸重合体、  (8) ① The weight average molecular weight is about 3,000 to about 100,000, ② The amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to about 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal lipoxyl group (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is 1 Lactic acid-glycolic acid polymer having a molecular weight of 200,000 or more and 3,000,000 or less,
(9) ①重量平均分子量が約 3, 000〜約 60， 000であり、 ②乳酸一グリ コール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイク 口モル） が約 20〜約 1000 mol (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸ーグリコール酸重合体の単位質量 （グ ラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 200， 0 00以上 3, 000， 000以下である乳酸ーグリコール酸重合体、  (9) ① The weight average molecular weight is about 3,000 to about 60,000, ② The amount of terminal lipoxyl groups (mole per mole) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 Approximately 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a molecular weight of not less than 1,200,000 and not more than 3,000,000,
(10) ①重量平均分子量が約 3, 000〜約 60， 000であり、 ②乳酸―グリ コール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイク 口モル） が約 40〜約 1000 mol (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 （グ ラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 200， 0 00以上 3, 000， 000以下である乳酸ーグリコール酸重合体、 (11) ①重量平均分子量が約 3， 000〜約 50, 000であり、 ②乳酸一ダリ コール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイク 口モル） が約 2 0〜約 1 000 DIOI (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 （グ ラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 200, 0 00以上 3， 000, 000以下である乳酸ーグリコール酸重合体、 (10) ① The weight-average molecular weight is about 3,000 to about 60,000, ② The amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (mole mole) is about 40 to Approximately 1000 mol (micromol), and (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the amount (micromol) of terminal lipoxyl groups per unit mass (gram) of lactic acid-dalicholic acid polymer A lactic acid-glycolic acid polymer having a product of not less than 1,200,000 and not more than 3,000,000, (11) ① The weight average molecular weight is about 3,000 to about 50,000, ② The amount of terminal carboxyl groups per unit mass (gram) of mono-lactic acid-dalicholic acid (gram) is about 20%. Approximately 1 000 DIOI (micromol), and (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer Lactic acid-glycolic acid polymer having a product of 1,200,000 or more and 3,000,000 or less,
(12) ①重量平均分子量が約 3， 000〜約 50, 000であり、 ②乳酸—ダリ コール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイク 口モル） が約 40〜約 1 000 mol (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸 -グリコール酸重合体の単位質量 （グ ラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1, 2 00, 0 00以上 3， 000, 000以下である乳酸—グリコール酸重合体、  (12) ① The weight-average molecular weight is about 3,000 to about 50,000, ② The amount of terminal carboxyl groups per unit mass (gram) of lactic acid-dalicholate polymer is about 40 to It is about 1 000 mol (micromol), and (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a product of not less than 1,200,000 and not more than 3,000,000,
(13) ①重量平均分子量が約 20， 000〜約 50， 000であり、 ②乳酸—グ リコール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイ クロモル） が約 20〜約 1 00 0 /zmol (マイクロモル） であり、 かつ③乳酸— ダリコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 (グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 200, 000以上 3， 000, 000以下である乳酸—グリコ一ル酸重合体、 および (13) ① The weight average molecular weight is about 20,000 to about 50,000, ② The amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 to about 100000 / zmol (micromol), and ③ the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer. Lactic acid-glycolic acid polymer having a product of not less than 1,200,000 and not more than 3,000,000, and
(14) ①重量平均分子量が約 20, 000〜約 5 0， 000であり、 ②乳酸—グ リコール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイ クロモル） が約 40〜約 1 0 0 0 zmol (マイクロモル） であり、 かつ③乳酸— ダリコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 (グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1, 200, 000以上 3， 000， 000以下である乳酸ーグリコール酸重合体などが好ま しい例としてあげられる。 (14) ① The weight-average molecular weight is about 20,000 to about 50,000, ② The terminal lipoxyl group amount (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 And about 3,000 zmol (micromol), and (3) the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal lipoxyl groups per unit mass (gram) of lactic acid-dalicholic acid polymer (micromoles) Lactic acid-glycolic acid polymer with a product of 1,200,000 or more and 3,000,000 or less is a preferable example.
さらに好ましい例としては、  As a more preferred example,
(15) ①重量平均分子量が約 3， 0 00〜約 1 0 0， 000であり、 ②乳酸—グ リコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 （グ ラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 500, 0 00以上 2， 600, 000以下である乳酸—グリコール酸重合体、 (15) ① The weight average molecular weight is about 3,000 to about 100,000, ② The weight average molecular weight of lactic acid-glycolic acid polymer and the unit mass of Lactic acid-glycolic acid polymer having a product of terminal lipoxyl group amount (micromol) per ram) of not less than 1,500,000 and not more than 2,600,000,
(16) ①重量平均分子量が約 3 , 000〜約 60 , 000であり、 ②乳酸—グリ コール酸重合体の重量平均分子量と乳酸ーグリコール酸重合体の単位質量 （ダラ ム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 500, 00 0以上 2， 600， 000以下である乳酸ーグリコ一ル酸重合体、  (16) ① The weight average molecular weight is about 3,000 to about 60,000, ② The weight average molecular weight of lactic acid-glycolic acid polymer and the terminal force per unit mass (daram) of lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a product of lipoxyl group content (micromol) of not less than 1,500,000 and not more than 2,600,000,
(17) ①重量平均分子量が約 3, 000〜約 50， 000であり、 ②乳酸—ダリ コール酸重合体の重量平均分子量と乳酸ーグリコール酸重合体の単位質量 （ダラ ム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1, 500, 00 0以上 2， 600， 000以下である乳酸ーグリコール酸重合体、  (17) (1) The weight average molecular weight is about 3,000 to about 50,000, (2) The weight average molecular weight of lactic acid-dalicholate polymer and the terminal carboxyl per unit mass (dalam) of lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a product of base amounts (micromoles) of not less than 1,500,000 and not more than 2,600,000,
(18) ①重量平均分子量が約 20， 000〜約 50， 000であり、 ②乳酸一グ リコール酸重合体の重量平均分子量と乳酸 -ダリコール酸重合体の単位質量 （グ ラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1, 500， 0 00以上 2， 600, 000以下である乳酸ーグリコール酸重合体、  (18) ① The weight average molecular weight is about 20,000 to about 50,000, ② The weight average molecular weight of lactic acid-glycolic acid polymer and the terminal weight per unit mass (gram) of lactic acid-daricholic acid polymer A lactic acid-glycolic acid polymer having a product of the amount of carboxyl groups (micromoles) of not less than 1,500,000 and not more than 2,600,000,
(19) ①乳酸—グリコール酸重合体の単位質量 （グラム） 当たりの末端のカルボ キシル基量 （マイクロモル） が約 20〜約 1000 mol (マイクロモル） であ り、 ②乳酸ーグリコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体 の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 500， 000以上 2, 600, 000以下である乳酸ーグリコール酸重合 体、 (19) ① The amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 to about 1000 mol (micromol), and ② the lactate-glycolic acid polymer A lactic acid-glycolic acid polymer in which the product of the weight average molecular weight and the amount of terminal carboxyl groups (micromoles) per unit mass (gram) of lactic acid-dalicholic acid polymer is from 1,500,000 to 2,600,000;
(20) ①乳酸ーグリコール酸重合体の単位質量 （グラム） 当たりの末端の力ルポ キシル基量 （マイクロモル） が約 40〜約 1000 zmol (マイクロモル） であ り、 ②乳酸一ダリコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体 の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1, 500, 000以上 2， 600， 000以下である乳酸—グリコール酸重合 体、  (20) ① The amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to about 1000 zmol (micromol); ② Lactic acid-dalicholate polymer Lactic acid-glycolic acid whose product is the weight-average molecular weight of the product and the amount of terminal lipoxyl groups (micromoles) per unit mass (gram) of lactic acid-dalicholic acid polymer is from 1,500,000 to 2,600,000 Polymer,
(21) ①重量平均分子量が約 3， 000〜約 100， 000であり、 ②乳酸—グ リコール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイ クロモル） が約 20〜約 1000 iinol (マイクロモル） であり、 かつ③乳酸一 グリコール酸重合体の重量平均分子量と乳酸 -グリコール酸重合体の単位質量(21) ① The weight average molecular weight is about 3,000 to about 100,000, ② The amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (My Chromol) is about 20 to about 1000 iinol (micromol), and (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the unit mass of lactic acid-glycolic acid polymer
(グラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 500, 000以上 2, 600， 000以下である乳酸—グリコール酸重合体、 Lactic acid-glycolic acid polymer having a product of terminal carboxyl group amount (micromol) per (gram) of not less than 1,500,000 and not more than 2,600,000,
(22) ①重量平均分子量が約 3, 000〜約 100, 000であり、 ②乳酸—グ リコール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイ クロモル） が約 40〜約 1000 mol (マイクロモル） であり、 かつ③乳酸一 グリコール酸重合体の重量平均分子量と乳酸 -グリコール酸重合体の単位質量(22) ① The weight average molecular weight is about 3,000 to about 100,000, ② The amount of terminal lipoxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to Approximately 1000 mol (micromol), and ③ weight average molecular weight of lactic acid-glycolic acid polymer and unit mass of lactic acid-glycolic acid polymer
(グラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 500, 000以上 2, 600， 000以下である乳酸—グリコール酸重合体、 Lactic acid-glycolic acid polymer having a product of terminal lipoxyl group amount (micromol) per (gram) of not less than 1,500,000 and not more than 2,600,000,
(23) ①重量平均分子量が約 3， 000〜約 60， 000であり、 ②乳酸一ダリ コール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイク 口モル） が約 20〜約 1000 mol (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量（グ ラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1, 500, 0 00以上 2， 600， 000以下である乳酸—グリコール酸重合体、  (23) (1) The weight average molecular weight is about 3,000 to about 60,000, and (2) The amount of terminal lipoxyl groups (mole per mole) per unit mass (gram) of lactate-dalicholate polymer is about 20. About 1000 mol (micromol), and (3) the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer A lactic acid-glycolic acid polymer having a product of not less than 1,500,000 and not more than 2,600,000,
(24) ①重量平均分子量が約 3 , 000〜約 60 , 000であり、 ②乳酸ーグリ コール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイク 口モル） が約 40〜約 1000 mol (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸ーグリコール酸重合体の単位質量 （グ ラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1, 500， 0 00以上 2， 600， 000以下である乳酸—グリコール酸重合体、  (24) ① The weight average molecular weight is about 3,000 to about 60,000, ② The amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (Mike mouth mole) is about 40 to about 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is 1 A lactic acid-glycolic acid polymer having a molecular weight of from 500,000 to 2,600,000,
(25) ①重量平均分子量が約 3, 000〜約 50, 000であり、 ②乳酸一グリ コール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイク 口モル） が約 20〜約 1000 mol (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸ーグリコール酸重合体の単位質量 （グ ラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 500, 0 00以上 2， 600， 000以下である乳酸ーグリコール酸重合体、 (26) ①重量平均分子量が約 3， 000〜約 50, 000であり、 ②乳酸―グリ コール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイク 口モル） が約 40〜約 1000 /zmol (マイクロモル） であり、 かつ③乳酸—グ リコール酸重合体の重量平均分子量と乳酸 -ダリコール酸重合体の単位質量（グ ラム） 当たりの末端の力ルポキシル基量 （マイクロモル） の積が 1， 500, 0 00以上 2， 600， 000以下である乳酸—グリコール酸重合体、 (25) ① The weight average molecular weight is about 3,000 to about 50,000, ② The amount of terminal carboxyl groups per unit mass (gram) of lactic acid-glycolic acid polymer (mike mole) is about 20 to Approximately 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer A lactic acid-glycolic acid polymer having a molecular weight of not less than 1,500,000 and not more than 2,600,000, (26) ① The weight-average molecular weight is about 3,000 to about 50,000, ② The terminal lipoxyl group amount per unit mass (gram) of lactic acid-glycolic acid polymer (Mike mouth mole) is about 40. About 1000 / zmol (micromol), and (3) the weight-average molecular weight of lactic acid-glycolic acid polymer and the amount of terminal lipoxyl group per unit mass (gram) of lactic acid-daricholic acid polymer (micromol) ) Is a lactic acid-glycolic acid polymer having a product of not less than 1,500,000 and not more than 2,600,000,
(27) ①重量平均分子量が約 20， 000〜約 50， 000であり、 ②乳酸—グ リコール酸重合体の単位質量 （グラム） 当たりの末端の力ルポキシル基量 （マイ クロモル） が約 20〜約 1000 mol (マイクロモル） であり、 かつ③乳酸— ダリコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 (グラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 500, 000以上 2， 600， 000以下である乳酸—グリコール酸重合体、 および (27) ① The weight average molecular weight is about 20,000 to about 50,000, ② The terminal lipoxyl group amount (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 20 to It is about 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer is 1 Lactic acid-glycolic acid polymer having a molecular weight of 500,000 or more and 2,600,000 or less, and
(28) ①重量平均分子量が約 20, 000〜約 50, 000であり、 ②乳酸—グ リコール酸重合体の単位質量 （グラム） 当たりの末端のカルボキシル基量 （マイ クロモル） が約 40〜約 1000 mol (マイクロモル） であり、 かつ③乳酸— ダリコール酸重合体の重量平均分子量と乳酸一ダリコール酸重合体の単位質量 (グラム） 当たりの末端のカルボキシル基量 （マイクロモル） の積が 1， 500, 000以上 2， 600， 000以下である乳酸—グリコール酸重合体などがあげ られる。 (28) ① The weight average molecular weight is about 20,000 to about 50,000, ② The amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-glycolic acid polymer is about 40 to about 1000 mol (micromol), and (3) the product of the weight average molecular weight of lactic acid-daricholic acid polymer and the amount of terminal carboxyl groups (micromol) per unit mass (gram) of lactic acid-dalicholic acid polymer is 1, Lactic acid-glycolic acid polymers having a molecular weight of 500,000 or more and 2,600,000 or less are exemplified.
本明細書における重量平均分子量、 数平均分子量および分散度とは、 重量平均 分子量が 1， 110， 000、 707， 000、 455， 645、 354, 00 0、 189, 000、 156, 055、 98， 900、 66， 437、 37， 2 00、 17， 100、 9， 830、 5， 870、 2, 500、 1， 303、 50 4の 15種類の単分散ポリスチレンを基準物質としてゲルパーミエ一シヨンク 口マトグラフィー （GPC) で測定したポリスチレン換算の分子量および算出し た分散度をいう。 測定は、 高速 GPC装置 （東ソ一製、 HLC— 8120GPC、 検出方式は示差屈折率による） 、 GPCカラム KF 804LX 2 (昭和電工製） を使用し、 移動相としてクロ口ホルムを用いる。 流速は lm 1 Zm i nでおこな ラ。 The weight-average molecular weight, number-average molecular weight and dispersity in the present specification mean that the weight-average molecular weight is 1,110,000, 707,000, 455,645, 354,000, 189,000, 156,055, 98, Gel permeation mouth chromatography using fifteen monodisperse polystyrenes as reference materials: 900, 66, 437, 37, 200, 17, 100, 9, 830, 5, 870, 2,500, 1, 303, 504 The molecular weight in terms of polystyrene measured by (GPC) and the calculated degree of dispersion. The measurement is performed using a high-speed GPC device (Tosoichi, HLC-8120GPC, detection method depends on the differential refractive index), GPC column KF804LX2 (Showa Denko), and chromatoform as the mobile phase. Flow rate is lm 1 Zmin. La.
本明細書における遊離のカルボキシル基量とはラベル化法により求めたもの (以下、 「ラベル化法によるカルボキシル基量」 と称する） をいう。 具体的にポ リ乳酸の場合について述べると、 ポリ乳酸 Wmgを 5N塩酸/ァセトニトリル (vZv = 4Z96) 混液 2m 1に溶解し、 0. 01M o—二トロフエニルヒ ドラジン塩酸塩 （ONPH) 溶液 （5N塩酸 Zァセトニトリル Zエタノール == 1. 02Z35Z15) 2m 1と 0. 15M 1—ェチルー 3— （ 3—ジメチルアミ ノプロピル） —カルポジイミド塩酸塩溶液 （ピリジン Zエタノール =4 vZ96 v) 2mlを加えて 40°Cで 30分反応させた後溶媒を留去する。残滓を水洗（4 回） した後、 ァセトニトリル 2m 1で溶解し、 0. 5mo 1 / 1のエタノール性 水酸化カリウム溶液 lm 1を加えて 60 で 30分反応させる。 反応液を 1. 5 N水酸化ナトリゥム水溶液で希釈して Ym 1とし、 1. 5 N水酸化ナトリゥム水 溶液を対象として 544 nm吸光度 A (/cm) を測定する。 一方、 DL—乳酸 水溶液を基準物質として、 その遊離カルボキシル基量 Cmo lZLをアルカリ 滴定で求め、 また ONPHラベル化法で DL—乳酸ヒドラジドとしたときの 54 4nm吸光度を B (/cm) とするとき、 重合体の単位質量 （グラム） あたり の遊離のカルボキシル基のモル量は以下の数式で求められる。  In the present specification, the amount of free carboxyl groups means a value obtained by a labeling method (hereinafter, referred to as “amount of carboxyl groups by labeling method”). Specifically, in the case of polylactic acid, polylactic acid Wmg is dissolved in 2 ml of a 5N hydrochloric acid / acetonitrile (vZv = 4Z96) mixed solution, and a 0.01 M o-ditrophenylhydrazine hydrochloride (ONPH) solution (5N hydrochloric acid Z Acetonitrile Z ethanol == 1.02Z35Z15) 2 ml and 0.15 M 1-Ethyl-3- (3-dimethylaminopropyl) -carposimide hydrochloride solution (pyridine Z ethanol = 4 vZ96 v) Add 2 ml and add 30 min at 40 ° C After the reaction, the solvent is distilled off. After washing the residue with water (4 times), dissolve in 2 ml of acetonitrile, add 0.5 ml of ethanolic potassium hydroxide solution (lm 1), and react at 60 for 30 minutes. Dilute the reaction solution with 1.5 N aqueous sodium hydroxide solution to Ym 1, and measure the absorbance A (/ cm) at 544 nm using the 1.5 N aqueous sodium hydroxide solution. On the other hand, using the aqueous solution of DL-lactic acid as a reference substance, the amount of free carboxyl groups CmolZL is determined by alkali titration, and when the absorbance at 544 nm when DL-lactic acid hydrazide is used in the ONPH labeling method is defined as B (/ cm). The molar amount of free carboxyl groups per unit mass (gram) of the polymer is determined by the following formula.
[COOH] (mo 1 /g) = (AYC) / (WB)  [COOH] (mo 1 / g) = (AYC) / (WB)
また、 該 「力ルポキシル基量」 は乳酸—グリコール酸重合体をトルエン—ァセ トン一メタノール混合溶媒に溶解し、 フエノールフタレインを指示薬としてこの 溶液をアルコール性水酸化カリウム溶液でカルボキシル基を滴定して求めるこ ともできる （以下、 この方法によって求めた値を 「アルカリ滴定法によるカルボ キシル基量」 と称する） 。  The “amount of lipoxyl group” is determined by dissolving a lactic acid-glycolic acid polymer in a mixed solvent of toluene-acetone / methanol, and titrating the carboxyl group with an alcoholic potassium hydroxide solution using phenolphthalein as an indicator. (Hereinafter, the value obtained by this method is referred to as “the amount of carboxyl group by the alkali titration method”).
乳酸一ダリコール酸重合体の分解 ·消失速度は共重合組成、 分子量あるいは遊 離力ルポキシル基量によって大きく変化するが、 一般的にはグリコール酸分率が 低いほど分解 ·消失が遅いため、 ダリコール酸分率を低くするかあるいは分子量 を大きくし、 かつ遊離力ルポキシル基量を少なくすることによって放出期間を長 くすることができる。 該 「乳酸ーグリコール酸重合体」 は、 例えば、 乳酸とグリコール酸からの無触 媒脱水重縮合 （特開昭 6 1— 2 8 5 2 1号） あるいはラクチドとグリコリド等の 環状ジエステル化合物からの触媒を用いた開環重合 （Encyc lopedic Handbook of Biomater ials and Bioengineer ing Part A: Mater ial s, Volume 2, Marcel Dekker, Inc. 1995年)で製造できる。 上記の公知の開環重合方法によって得られる重合体 は、 得られる重合体の末端に遊離のカルボキシル基を有しているとは限らないが、 例えば、 E P— A— 0 8 3 9 5 2 5号に記載の加水分解反応に付すことにより、 単位質量当たりにある程度のカルボキシル基量を有する重合体に改変すること ができ、 これを用いることもできる。 The rate of decomposition and disappearance of the lactic acid-dalicholic acid polymer varies greatly depending on the copolymer composition, molecular weight and the amount of the free lipoxyl group, but in general, the lower the glycolic acid fraction, the slower the decomposition and disappearance. The release period can be prolonged by lowering the fraction or increasing the molecular weight and reducing the amount of free lipoxyl groups. The “lactic acid-glycolic acid polymer” is, for example, a non-catalytic dehydration polycondensation of lactic acid and glycolic acid (Japanese Patent Application Laid-Open No. 61-28521) or a catalyst derived from lactide and a cyclic diester compound such as glycolide. Can be produced by ring-opening polymerization using a compound (Encyclopedic Handbook of Biomaterials and Bioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc. 1995). The polymer obtained by the above-mentioned known ring-opening polymerization method does not necessarily have a free carboxyl group at the terminal of the obtained polymer. For example, EP-A-08399525 By subjecting the polymer to the hydrolysis reaction described in (1), the polymer can be modified into a polymer having a certain amount of carboxyl group per unit mass, and this can also be used.
上記の 「末端に遊離のカルボキシル基を有する乳酸ーグリコール酸重合体」 は 公知の製造法（例えば無触媒脱水重縮合法、特開昭 6 1 - 2 8 5 2 1号公報参照） で問題なく製造でき、 あるいは、 下記の方法によっても製造できる。  The above “lactic acid-glycolic acid polymer having a free carboxyl group at the terminal” can be produced by a known production method (for example, a non-catalytic dehydration polycondensation method, see Japanese Patent Application Laid-Open No. 61-28521) without any problem. Alternatively, it can be produced by the following method.
( 1 ) まず、 カルボキシル基が保護されたヒドロキシモノカルボン酸誘導体 （例、 D—乳酸 tert-プチル、 L一乳酸べンジルなど） またはカルボキシル基が保護さ れたヒドロキシジカルボン酸誘導体 （例、 タルトロン酸ジベンジル、 2—ヒドロ キシェチルマロン酸ジ ter t-ブチルなど） の存在下、 重合触媒を用いて環状エス テル化合物を重合反応に付す。  (1) First, a hydroxymonocarboxylic acid derivative having a protected carboxyl group (eg, tert-butyl D-lactic acid, benzyl L-lactate) or a hydroxydicarboxylic acid derivative having a protected carboxyl group (eg, tartronic acid) The cyclic ester compound is subjected to a polymerization reaction using a polymerization catalyst in the presence of dibenzyl, ditert-butyl 2-hydroxymalonate, and the like.
上記の 「力ルポキシル基が保護されたヒドロキシモノカルボン酸誘導体」 また は 「カルボキシル基が保護されたヒドロキシジカルボン酸誘導体」 とは、 例えば、 力ルポキシル基 （― C O OH) がアミド （一 C〇NH 2) 化またはエステル （― C OO R) 化されているヒドロキシカルボン酸誘導体などがあげられるが、 なか でも、 カルボキシル基 （― C O OH) がエステル （― C OO R) 化されているヒ ドロキシカルボン酸誘導体などが好ましい。 The term “hydroxylcarboxylic acid derivative having a protected carboxylic acid group” or “hydroxydicarboxylic acid derivative having a protected carboxyl group” refers to, for example, a compound in which the carboxylic acid group (—CO OH) is an amide (1-C〇NH) 2 ) Hydroxy carboxylic acid derivatives which are esterified or esterified (-COOR) are listed. Among them, the hydroxy group in which the carboxyl group (-COOH) is esterified (-COOR) is preferable. Carboxylic acid derivatives are preferred.
ここでエステルにおける Rとしては、 例えば、 メチル、 ェチル、 n—プロピル、 イソプロピル、 n—ブチル、 tert—ブチルなどの（^ - 6アルキル基、 例えば、 シ クロペンチル、 シクロへキシルなどの C 3— 8シクロアルキル基、 例えば、 フエ二 ル、 α—ナフチルなどの C 6_ 1 27リール基、 例えば、 ベンジル、 フエネチルなど のフエ二ルー C ト 2アルキル基もしくは α—ナフチルメチルなどの α—ナフチル 一（：卜2アルキル基などの 4ァラルキル基などがあげられる。 なかでも、 t er t -ブチル基、 ベンジル基などが好ましい。 Here, as R in the ester, e.g., methyl, Echiru, n- propyl, isopropyl, n- butyl, such as tert- butyl (^ - 6 alkyl group, for example, shea Kuropenchiru, C 3, such as cyclohexyl - 8 cycloalkyl groups such as phenylene Le, alpha-C 6 _ 1 2 7 aryl group such as naphthyl, for example, benzyl, such as phenethyl phenylene route C DOO 2 alkyl or alpha-naphthylmethyl etc. alpha-naphthyl One (: a 4- aralkyl group such as a 2- alkyl group, etc. Among them, a tert-butyl group, a benzyl group and the like are preferable.
該 「環状エステル化合物」 とは、 例えば環内に少なくとも 1つのエステル結合 を有する環状化合物をいう。具体的には、環状モノエステル化合物（ラクトン類） または環状ジエステル化合物 （ラクチド類） などがあげられる。  The “cyclic ester compound” refers to, for example, a cyclic compound having at least one ester bond in a ring. Specific examples include cyclic monoester compounds (lactones) and cyclic diester compounds (lactides).
該 「環状モノエステル化合物」 としては、 例えば、 4員環ラクトン （/3—プロ ピオラクトン、 3—ブチロラクトン、 /3 _イソバレロラクトン、 ）3—力プロラク トン、 _イソ力プロラクトン、 ）3—メチルー ]3—バレロラクトンなど） 、 5員 環ラクトン （ァ一プチロラクトン、 ァ一バレロラクトンなど） 、 6員環ラクトン ( <5—バレロラクトンなど） 、 7員環ラクトン （ε —力プロラクトンなど） 、 Ρ- ジォキサノン、 1 , 5-ジォキセパン一 2—オンなどがあげられる。 該 「環状ジエステル化合物」 としては、  Examples of the “cyclic monoester compound” include 4-membered lactones (/ 3-propiolactone, 3-butyrolactone, / 3-isovalerolactone,) 3-force prolactone, _isoforce prolactone,) 3- Methyl-] 3-valerolactone, etc.), 5-membered lactones (such as aptyloractone, a-valerolactone), 6-membered lactones (such as <5-valerolactone), and 7-membered lactones (such as ε-force prolactone) , Ρ-dioxanone, 1,5-dioxepan-2-one and the like. As the “cyclic diester compound”,
例えば、 式  For example, the expression
Figure imgf000020_0001
Figure imgf000020_0001
(式中、 R 'および R2はそれぞれ同一または異なって、 水素原子またはメチル、 ェチル、 n—プロピル、 イソプロピル、 n—プチル、 t 一ブチルなどの ァ ルキル基を示す） で表される化合物などがあげられ、 なかでも、 R 1が水素原子 で R 2がメチル基、 R 1および R 2がそれぞれ水素原子であるラクチドなどが好ま しい。 (Wherein, R 'and R 2 are the same or different and each is a hydrogen atom or a methyl, Echiru, n-propyl, isopropyl, n- heptyl, showing a § alkyl group such as t one-butyl) compound represented by such as Of these, lactide in which R 1 is a hydrogen atom, R 2 is a methyl group, and R 1 and R 2 are each a hydrogen atom is preferred.
具体的には、 たとえばグリコリド、 L-ラクチド、 D-ラクチド、 DL-ラクチド、 mes o-ラクチド、 3-メチル -1 , 4-ジォキサン- 2, 5-ジオン （光学活性体も含む） な どがあげられる。  Specifically, for example, glycolide, L-lactide, D-lactide, DL-lactide, meso-lactide, 3-methyl-1,4-dioxane-2,5-dione (including optically active forms), etc. can give.
該 「重合触媒」 としては、 例えば有機スズ系触媒 （例、 ォクチル酸スズ、 ジラ ゥリル酸ジ _ n—プチルスズ、 テトラフエニルスズなど） 、 アルミ系触媒 （例、 卜リエチルアルミニウムなど） 、 亜鉛系触媒 （例、 ジェチル亜鉛など） などがあ け'られる。 Examples of the “polymerization catalyst” include organotin-based catalysts (eg, tin octylate, di-n-butyltin diphenylate, tetraphenyltin, etc.), aluminum-based catalysts (eg, triethylaluminum, etc.), zinc Based catalysts (eg, getyl zinc, etc.) '
反応後の除去の容易さの観点からは、 アルミ系触媒、 亜鉛系触媒が好ましく、 さらには、 残存した場合の安全性の観点からは亜鉛系触媒が好ましい。  Aluminum-based catalysts and zinc-based catalysts are preferred from the viewpoint of ease of removal after the reaction, and zinc-based catalysts are more preferred from the viewpoint of safety when remaining.
重合触媒の溶媒としては、 ベンゼン、 へキサン、 トルエンなどが用いられ、 中 でもへキサン、 トルエンなどが好ましい。  As a solvent for the polymerization catalyst, benzene, hexane, toluene and the like are used, among which hexane and toluene are preferable.
「重合方法」 は、 反応物を融解状態にして行う塊状重合法または反応物を適当 な溶媒 （例えば、 ベンゼン、 トルエン、 キシレン、 デカリン、 ジメチルホルムァ ミドなど） に溶解して行う溶液重合法を用いればよい。 溶媒としては、 トルエン、 キシレンなどが好ましい。 重合温度は特に限定されるものではないが、 塊状重合 の場合、 反応開始時に反応物を融解状態に至らしめる温度以上、 通常 1 0 0〜3 0 0 °Cであり、 溶液重合の場合、 通常室温〜 1 5 0 °Cであり、 反応温度が反応溶 液の沸点を越えるときは、 凝縮器を付けて還流するか、 または耐圧容器内で反応 させればよい。 重合時間は重合温度、 そのほかの反応条件や目的とする重合体の 物性などを考慮して適宜定められるが、 例えば 1 0分〜 7 2時間である。 反応後 は、 必要であれば反応混合物を適当な溶媒 （例えば、 アセトン、 ジクロロメタン、 クロ口ホルムなど） に溶解し、 酸 （例えば、 塩酸、 無水酢酸、 トリフルォロ酢酸 など） で重合を停止させた後、 常法によりこれを目的物を溶解しない溶媒 （例え ば、 アルコール、 水、 エーテル、 イソプロピルエーテルなど） 中に混合するなど して析出させ、 ω端に保護されたカルボキシル基を有する乳酸ーグリコール酸重 合体を単離すればよい。  The “polymerization method” refers to a bulk polymerization method in which the reactants are melted or a solution polymerization method in which the reactants are dissolved in an appropriate solvent (for example, benzene, toluene, xylene, decalin, dimethylformamide, etc.). It may be used. As the solvent, toluene, xylene and the like are preferable. The polymerization temperature is not particularly limited.In the case of bulk polymerization, the temperature is not lower than the temperature at which the reactants are brought into a molten state at the start of the reaction, usually 100 to 300 ° C. When the reaction temperature is from room temperature to 150 ° C. and the reaction temperature exceeds the boiling point of the reaction solution, the reaction may be carried out by refluxing with a condenser or in a pressure vessel. The polymerization time is appropriately determined in consideration of the polymerization temperature, other reaction conditions, physical properties of the target polymer, and the like, and is, for example, 10 minutes to 72 hours. After the reaction, if necessary, dissolve the reaction mixture in a suitable solvent (eg, acetone, dichloromethane, chloroform, etc.) and terminate the polymerization with an acid (eg, hydrochloric acid, acetic anhydride, trifluoroacetic acid, etc.). This is precipitated by mixing it in a solvent that does not dissolve the target substance (eg, alcohol, water, ether, isopropyl ether, etc.) according to a conventional method, and is precipitated by lactic acid-glycolic acid having a carboxyl group protected at the ω-terminal. The combination may be isolated.
本願の重合方法は、 従来のメタノールなどのいわゆるプロトン性連鎖移動剤の 代わりにカルボキシル基が保護されたヒドロキシカルボン酸誘導体 （例、 D—乳 酸 tert -プチル、 L一乳酸べンジルなど） またはカルボキシル基が保護されたヒ ドロキシジカルボン酸誘導体 （例、 タルトロン酸ジベンジル、 2—ヒドロキシェ チルマロン酸ジ tert-ブチルなど） などが用いられる。  The polymerization method of the present application is based on a hydroxycarboxylic acid derivative having a protected carboxyl group (eg, tert-butyl D-lactate, benzyl L-lactate) or a carboxyl group instead of a so-called protic chain transfer agent such as methanol. A hydroxydicarboxylic acid derivative having a protected group (eg, dibenzyl tartronate, ditert-butyl 2-hydroxyethylmalonate) and the like are used.
このように力ルポキシル基が保護されたヒドロキシカルボン酸誘導体 （例、 D 一乳酸 tert-プチル、 L一乳酸べンジルなど） または力ルポキシル基が保護され たヒドロキシジカルボン酸誘導体 （例、 タルトロン酸ジベンジル、 2—ヒドロキ シェチルマロン酸ジ ter t-ブチルなど） などをプロトン性連鎖移動剤に用いるこ とによって、 ①分子量を仕込み組成によって制御でき、 ②重合後に脱保護反応に 付すことによって、 得られる乳酸—グリコール酸重合体の ω端にカルボキシル基 を遊離させることができる。 In this manner, hydroxycarboxylic acid derivatives having a protected olepoxyl group (eg, tert-butyl D-lactate, benzyl L-lactate) or hydroxydicarboxylic acid derivatives having a protected propyloxyl group (eg, dibenzyl tartronate, 2-hydroxy By using di-tert-butyl shetyl malonate, etc.) as a protic chain transfer agent, ① the molecular weight can be controlled by the charge composition, and ② the lactic acid-glycolic acid polymer obtained by subjecting it to a deprotection reaction after polymerization. A carboxyl group can be liberated at the ω-end.
( 2 ) 次に、 上記 （1 ) の重合反応によって得られた ω端に保護されたカルボキ シル基を有する乳酸ーグリコール酸重合体を脱保護反応に付すことにより目的 とする ω端に遊離の力ルポキシル基を有する乳酸ーグリコール酸重合体を得る ことができる。  (2) Next, by subjecting the lactic acid-glycolic acid polymer having a carboxyl group protected at the ω end obtained by the polymerization reaction (1) above to a deprotection reaction, the desired free force at the ω end is obtained. A lactic acid-glycolic acid polymer having a lipoxyl group can be obtained.
該保護基は自体公知の方法により脱離できる。 このような方法としては、 ポリ (ヒドロキシカルボン酸） のエステル結合に影響を与えずに保護基を除去するこ とが可能な方法であればいずれを用いてもよいが、 具体的には、 例えば還元、 酸 分解などの方法が挙げられる。  The protecting group can be removed by a method known per se. As such a method, any method can be used as long as the protecting group can be removed without affecting the ester bond of the poly (hydroxycarboxylic acid). Methods such as reduction and acid decomposition are mentioned.
該還元方法としては、 例えば触媒 （例、 パラジウム炭素、 パラジウム黒、 酸化 白金など） を用いる接触還元、 液体アンモニゥム中でのナトリウムによる還元、 ジチオスレィトールによる還元などが挙げられる。 例えば、 ω端にベンジル基で 保護されたカルボキシル基を有するポリマーを接触還元する場合、 具体的にはポ リマーを酢酸ェチル、 ジクロロメタン、 クロ口ホルムなどに溶解したものにパラ ジゥム炭素を添加し、 激しく攪拌しながら室温で水素を約 2 0分〜約 4時間通気 することで脱保護できる。  Examples of the reduction method include catalytic reduction using a catalyst (eg, palladium carbon, palladium black, platinum oxide, etc.), reduction with sodium in liquid ammonium, reduction with dithiothreitol, and the like. For example, in the case of catalytic reduction of a polymer having a carboxyl group protected by a benzyl group at the ω end, specifically, palladium carbon is added to a polymer dissolved in ethyl acetate, dichloromethane, chloroform, etc. Deprotection can be achieved by bubbling hydrogen for about 20 minutes to about 4 hours at room temperature with vigorous stirring.
酸分解方法としては、 例えば無機酸 （例、 フッ化水素、 臭化水素、 塩化水素な ど） あるいは有機酸 （例、 トリフルォロ酢酸、 メタンスルホン酸、 トリフルォロ メタンスルホン酸など） またはこれらの混合物などによる酸分解などが挙げられ る。 また、 必要に応じて、 酸分解の際、 カチオン ·スカベンジャー （例、 ァニソ ール、 フエノール、 チオア二ソ一ルなど） を適宜添加してもよい。 例えば、 ω端 に ter t-ブチル基で保護されたカルボキシル基を有するポリマーを酸分解する場 合、 具体的にはポリマーをジクロロメタン、 キシレン、 トルエンなどに溶解した ものにトリフルォロ酢酸を適当量加えて、 あるいはポリマーをトリフルォロ酢酸 で溶解して室温で約 1時間攪拌することで脱保護できる。 好ましくは、 該酸分解法は重合反応直後に行ってもよく、 その場合は重合停止 反応を兼ねることができる。 The acid decomposition method includes, for example, an inorganic acid (eg, hydrogen fluoride, hydrogen bromide, hydrogen chloride, etc.) or an organic acid (eg, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.) or a mixture thereof. Acid decomposition and the like. If necessary, a cation scavenger (eg, anisol, phenol, thioanisole, etc.) may be appropriately added during acid decomposition. For example, when acid-decomposing a polymer having a carboxyl group protected by a tert-butyl group at the ω-end, specifically, adding an appropriate amount of trifluoroacetic acid to a solution of the polymer in dichloromethane, xylene, toluene, etc. Alternatively, deprotection can be achieved by dissolving the polymer in trifluoroacetic acid and stirring for about 1 hour at room temperature. Preferably, the acid decomposition method may be carried out immediately after the polymerization reaction, in which case it can also serve as a polymerization termination reaction.
さらに必要に応じて、 上記の脱保護反応によつて得られた乳酸—グリコール酸 重合体を酸加水分解反応に付すことにより、 該乳酸一ダリコール酸重合体の重量 平均分子量、 数平均分子量あるいは末端カルボキシル基量を目的に応じて調節す ることができる。 具体的には、 例えば、 E P—A—0 8 3 9 5 2 5号に記載の方 法またはそれに準じた方法によって行うことができる。  Further, if necessary, the lactic acid-glycolic acid polymer obtained by the above deprotection reaction is subjected to an acid hydrolysis reaction, whereby the weight average molecular weight, the number average molecular weight or the terminal The amount of carboxyl groups can be adjusted according to the purpose. Specifically, it can be carried out, for example, by the method described in EP-A-0 839 525 25 or a method analogous thereto.
前記のようにして得られた乳酸一ダリコール酸重合体は、 徐放性製剤を製造す るための基剤として用いることができる。  The lactic acid-dalicholic acid polymer obtained as described above can be used as a base for producing a sustained-release preparation.
さらには末端に特定されない遊離のカルボキシル基を有する重合体は公知の 製造法 （例えば、 W〇9 4 Z 1 5 5 8 7号公報参照） で製造できる。  Furthermore, a polymer having a free carboxyl group that is not specified at the terminal can be produced by a known production method (for example, see WO94 / 15587).
また、 開環重合後の化学的処理によって末端を遊離の力ルポキシル基にした乳 酸ーグリコール酸重合体は例えばべ一リンガー インゲルハイム （Boehr inger Ingelheim KG) などから市販されているものを用いてもよい。  In addition, a lactate-glycolic acid polymer whose terminal is converted into a free lipoxyl group by a chemical treatment after ring-opening polymerization may be, for example, one commercially available from Boehringer Ingelheim KG or the like. Good.
乳酸—グリコール酸重合体は塩（乳酸—グリコール酸重合体の塩としては例え ば前述の塩などがあげられる） であってもよく、 その製造方法としては、 例えば、 The lactic acid-glycolic acid polymer may be a salt (as the salt of the lactic acid-glycolic acid polymer, for example, the above-mentioned salts, etc.).
( a ) 上記の力ルポキシル基を有する乳酸一ダリコール酸重合体を有機溶媒に溶 解したものと無機塩基 （例、 ナトリウム、 カリウム等のアルカリ金属、 カルシゥ ム、 マグネシウム等のアルカリ土類金属など） や有機塩基 （例、 トリェチルアミ ン等の有機アミン類、 アルギニン等の塩基性アミノ酸類等） のイオンを含む水溶 液を混合してイオン交換反応を行わせた後に、 塩となったポリマーを単離する方 法、 （b ) 上記の力ルポキシル基を有する乳酸ーグリコール酸重合体を有機溶媒 に溶解したものに上記 （a ) で列挙した塩基の弱酸塩 （例えば、 酢酸塩、 グリコ ール酸塩） を溶解した後に、 塩となった乳酸ーグリコール酸重合体を単離する方 法、 （C ) 上記の力ルポキシル基を有する乳酸ーグリコール酸重合体を有機溶媒 に溶解したものに遷移金属 （例， 亜鉛， 鉄， 銅など） の弱酸塩 （例えば、 酢酸塩、 グリコ一ル酸塩） もしくは酸化物を混合した後に塩となった乳酸ーグリコール酸 重合体を単離する方法、 などが挙げられる。 本発明の組成物における生理活性物質の重量比は、 生理活性物質の種類、 所望 の薬理効果および効果の持続期間などによって異なるが、 生理活性物質またはそ の塩とヒドロキシナフトェ酸またはその塩と乳酸—グリコ一ル酸重合体または その塩の三者を含有する徐放性組成物の場合、 その三者の和に対して、 例えば生 理活性ペプチドまたはその塩の場合、 約 0 . 0 0 1〜約5 0重量％、 好ましくは 約 0 . 0 2〜約 4 0重量％、 より好ましくは約 0 . 1〜3 0重量％、 最も好まし くは約 1 2〜 2 4重量％であり、 非べプチド性生理活性物質またはその塩の場合、 約 0 . 0 1〜8 0重量％、 好ましくは約 0 . 1〜5 0重量％である。 生理活性物 質のヒドロキシナフトェ酸塩を含む場合でも同様な重量比である。 生理活性ぺプ チド （仮に （A) と称する） とヒドロキシナフトェ酸 （仮に （B) と称する） と の塩を含有してなる徐放性組成物の場合、 （A) と （B) との塩の和に対して、 (A) の重量比は通常約 5〜約 9 0重量％、 好ましくは約 1 0〜約 8 5重量％、 より好ましくは約 1 5〜約 8 0重量％、 特に好ましくは約 3 0〜約 8 0重量％で ある。 (a) A solution obtained by dissolving the above-mentioned lactic acid-dalicolic acid polymer having a hydroxyl group in an organic solvent and an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, etc.) And an organic base (eg, organic amines such as triethylamine, basic amino acids such as arginine, etc.) mixed with an aqueous solution containing ions, and subjected to ion exchange reaction. (B) Weak acid salts of the bases listed in (a) above (eg, acetates, glycolates) in a solution of the lactic acid-glycolic acid polymer having the above-mentioned carboxylic acid group in an organic solvent. (C) dissolving the above-mentioned lactic acid-glycolic acid polymer having a lipoxyl group in an organic solvent Isolate lactic acid-glycolic acid polymer after mixing with a weak acid (eg, acetate, glycomonolate) or oxide of transition metal (eg, zinc, iron, copper, etc.) Method, and the like. The weight ratio of the physiologically active substance in the composition of the present invention varies depending on the kind of the physiologically active substance, the desired pharmacological effect and the duration of the effect, and the like. However, the physiologically active substance or its salt and hydroxynaphthoic acid or its salt In the case of a sustained-release composition containing a lactic acid-glycolic acid polymer or a salt thereof, the sum of the three is, for example, about 0.000 for a bioactive peptide or a salt thereof. From 1 to about 50% by weight, preferably from about 0.02 to about 40% by weight, more preferably from about 0.1 to 30% by weight, most preferably from about 12 to 24% by weight. In the case of a non-peptidic physiologically active substance or a salt thereof, the amount is about 0.01 to 80% by weight, preferably about 0.1 to 50% by weight. The weight ratio is the same even when a physiologically active substance, hydroxynaphthoate, is contained. In the case of a sustained-release composition containing a salt of a bioactive peptide (tentatively referred to as (A)) and hydroxynaphthoic acid (tentatively referred to as (B)), (A) and (B) (A) is usually about 5 to about 90% by weight, preferably about 10 to about 85% by weight, more preferably about 15 to about 80% by weight, Particularly preferred is about 30 to about 80% by weight.
生理活性物質またはその塩とヒドロキシナフトェ酸またはその塩と乳酸ーグ リコール酸重合体またはその塩の三者を含有する徐放性組成物の場合、 ヒドロキ シナフトェ酸またはその塩の配合量は、 好ましくは、 生理活性物質またはその塩 1モルに対して、 ヒドロキシナフトェ酸またはその塩が約 1 Z 2〜約 2モル、 約 3 / 4〜約4ダ3モル、 特に好ましくは約 4 / 5〜約 6 Z 5モルである。  In the case of a sustained-release composition containing a physiologically active substance or a salt thereof and hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof, the amount of hydroxyaphthoic acid or a salt thereof is as follows: Preferably, hydroxynaphthoic acid or a salt thereof is about 1 Z2 to about 2 mol, about 3/4 to about 4 da3 mol, particularly preferably about 4/5, per mol of a physiologically active substance or a salt thereof. About 6 Z 5 mol.
本発明の組成物の設計を、 生理活性物質、 ヒドロキシナフトェ酸および乳酸一 ダリコール酸重合体の三者を含有する徐放性組成物について、 生理活性物質が塩 基性である場合を例に用いて以下に述べる。 この場合、 組成物中には塩基として 生理活性物質が、 酸としてヒドロキシナフトェ酸が共存しており、 それらが遊離 体あるいは塩として組成物中に配合された場合のいずれにおいても、 組成物製造 時のある時点において含水状態あるいは微量の水の存在下でおのおの解離平衡 が成り立つている。 微水溶性のヒドロキシナフトェ酸が生理活性物質と形成する 塩は、 該生理活性物質の特性にもよるが微水溶性と考えられるため、 解離平衡は このような微水溶性塩形成の側に傾く。 塩基性の生理活性物質を高含量に含む組成物を製造するには、 上記解離平衡か ら考えて、 生理活性物質のほとんどをプロトン化して上記微水溶性塩にすること が望ましい。 このためには、 少なくとも生理活性物質またはその塩と当量に近い ヒドロキシナフトェ酸またはその塩を配合するのが望ましい。 The design of the composition of the present invention is based on the case where the bioactive substance is basic for a sustained-release composition containing a bioactive substance, hydroxynaphthoic acid, and a polymer of lactate-dalicholic acid. This will be described below. In this case, a bioactive substance as a base and hydroxynaphthoic acid as an acid coexist in the composition, and when they are incorporated in the composition as a free form or a salt, the composition is produced. At some point in time, dissociation equilibrium is established in the presence of water or in the presence of trace amounts of water. The salt formed by the slightly water-soluble hydroxynaphthoic acid with the physiologically active substance is considered to be slightly water-soluble depending on the properties of the physiologically active substance. Lean. In order to produce a composition containing a high content of a basic physiologically active substance, it is desirable to protonate most of the physiologically active substance to form the above slightly water-soluble salt in view of the above dissociation equilibrium. For this purpose, it is desirable to mix hydroxynaphthoic acid or a salt thereof that is at least equivalent to a physiologically active substance or a salt thereof.
次に、 組成物中に包含された生理活性物質の徐放機構を以下に述べる。 生理活 性物質は上記の配合組成ではほとんどがプロトン化されて、 対イオンを伴った状 態で存在している。 対イオンは、 主にヒドロキシナフトェ酸である。 組成物が生 体中に投与された後は、 乳酸一ダリコール酸重合体の分解によって経時的にその オリゴマーおよびモノマーが生成し始めるが、 生成するオリゴマー （乳酸一ダリ コール酸オリゴマー） およびモノマー （乳酸またはグリコール酸） は必ず 1個の カルボキシル基を有しており、 これらも生理活性物質の対イオンになり得る。 生 理活性物質の放出は電荷の移動を伴わない、 すなわち対イオンを伴った塩として 行われる力 移動可能な対イオン種としては上述のようにヒドロキシナフトェ酸、 乳酸一ダリコール酸オリゴマー（移動可能な程度の分子量の）およびモノマー（乳 酸またはグリコール酸） があげられる。  Next, the mechanism for sustained release of the physiologically active substance contained in the composition will be described below. Most of the physiologically active substances are protonated in the above-mentioned composition, and exist in a state with a counter ion. The counter ion is mainly hydroxynaphthoic acid. After the composition has been administered in vivo, the oligomers and monomers begin to form over time due to the degradation of the polymer of lactate-dalicholate, and the oligomers (lactate-dalicholate oligomer) and the monomers (lactate-lactic acid) are formed. Or glycolic acid) always has one carboxyl group, which can also be a counter ion of a physiologically active substance. The release of a bioactive substance does not involve the transfer of charge, ie, the force performed as a salt with a counter ion. As the movable counter ion species, as described above, hydroxynaphthoic acid, lactate-dalicholate oligomer To a certain degree of molecular weight) and monomers (lactic acid or glycolic acid).
複数の酸が共存する場合には、 その組成比にもよるが一般的に強酸の塩が優先 的に生ずる。 ヒドロキシナフトェ酸の p K aは、 例えば、 3—ヒドロキシー 2— ナフトェ酸のそれは 2 . 7 0 8 (化学便覧 基礎編 I I、 日本化学会、 昭和 4 4 年 9月 2 5日発行） である。 一方、 乳酸—グリコ一ル酸オリゴマーのカルポキシ ル基のそれは知られていないが、 乳酸またはグリコール酸の p K a (=3. 86または 3. 83)を基礎に、 「置換基導入による自由エネルギー変化は加成則で近似可能」 との原理に従って計算できる。 解離定数に対する置換基の寄与は求められており 利用することができる (Table 4. 1 in " pKa Predic t ion for Organi c Ac id and Bases" , D. D. Perr in, B. De即 sey and E. P. Serj eant, 1981) 。 ヒドロキシル基と エステル結合に対してはそれぞれ、  When a plurality of acids coexist, a salt of a strong acid generally occurs preferentially, depending on the composition ratio. The pK a of hydroxynaphthoic acid is, for example, that of 3-hydroxy-2-naphthoic acid is 2.708 (Chemical Handbook Basic Edition II, The Chemical Society of Japan, issued September 25, 1969) . On the other hand, the carboxyl group of the lactic acid-glycolic acid oligomer is not known, but based on the pK a (= 3.86 or 3.83) of lactic acid or glycolic acid, the “free energy due to the introduction of a substituent” The change can be approximated by the addition rule. " The contribution of substituents to the dissociation constant is required and can be used (Table 4.1 in "pK Prediction for Organic Acids and Bases", DD Perrin, B. De Immediate sey and EP Serj eant , 1981). For the hydroxyl group and the ester bond respectively
△ p K a (OH) = - 0 . 9 0  △ p Ka (OH) =-0.90
△ p K a (エステル結合） =— 1 . 7  △ p Ka (ester bond) = — 1.7
なので、 乳酸—グリコ一ル酸オリゴマーのカルボキシル基の p K aは、 解離基に 最も近いエステル結合の寄与を考慮して、 Therefore, the pKa of the carboxyl group of the lactic acid-glycolic acid oligomer is Considering the contribution of the closest ester bond,
pKa = pKa (乳酸またはグリコール酸）— ApKa (0H) + ApKa (エス テル結合） =3. 06または 3. 03と求められる。 従って、 ヒドロキシナフト ェ酸は乳酸 （pKa=3. 86) 、 グリコール酸 （pKa = 3. 83) 、 さらに は乳酸ーグリコール酸オリゴマーよりも強い酸であるから、 上記組成物中ではヒ ドロキシナフトェ酸と生理活性物質との塩が優先的に生成していると考えられ、 その塩の特性が、 組成物中からの生理活性物質の徐放特性を支配的に決定すると 考えられる。 該生理活性物質としては上述の生理活性物質などがあげられる。 ここにおいて、 ヒドロキシナフトェ酸が生理活性物質と形成する塩が微水溶性 であって水不溶性でないことが徐放機構に好影響をあたえる。 すなわち、 上記酸 解離定数の考察で明らかにしたように移動可能な生理活性物質の塩としては、 放 出の初期には上記乳酸一ダリコール酸オリゴマーおよびモノマーよりも強酸で あるヒドロキシナフトェ酸の塩が優勢に存在する結果、 その塩の溶解性、 体組織 への分配性が、 生理活性物質の放出速度の決定因子となるため、 ヒドロキシナフ トェ酸の配合量で薬物の初期放出パターンを調節し得る。 その後、 ヒドロキシナ フトェ酸の減少および乳酸ーグリコ一ル酸重合体の加水分解によって生ずるォ リゴマーおよびモノマーの増大に伴い、 オリゴマーおよびモノマーを対イオンと する生理活性物質の放出機構が徐々に優勢となり、 ヒドロキシナフトェ酸が事実 上該 「組成物」 から消失した場合でも安定な生理活性物質の放出が保たれる。 ま た、 徐放性組成物の製造時の生理活性物質の取り込み効率をあげること、 および 取り込まれた生理活性物質の投与後の初期過剰放出を抑制しうることも説明で さる。  pKa = pKa (lactic or glycolic acid) — ApKa (0H) + ApKa (ester bond) = 3.06 or 3.03. Therefore, hydroxynaphthoic acid is a stronger acid than lactic acid (pKa = 3.86), glycolic acid (pKa = 3.83), and lactic acid-glycolic acid oligomer. It is believed that the salt with the active substance is preferentially formed, and that the properties of the salt predominantly determine the sustained release properties of the bioactive substance from the composition. Examples of the physiologically active substance include the aforementioned physiologically active substances. Here, the fact that the salt formed by hydroxynaphthoic acid with the physiologically active substance is slightly water-soluble and not water-insoluble has a favorable effect on the sustained-release mechanism. That is, as clarified in the consideration of the acid dissociation constant, as a salt of a mobile physiologically active substance, in the early stage of release, a salt of hydroxynaphthoic acid, which is a stronger acid than the above-mentioned lactic acid-dalicholic acid oligomer and monomer, is used. Predominantly, the solubility of the salt and the distribution to the body tissue are determinants of the release rate of the bioactive substance, so the amount of hydroxynaphthoic acid controls the initial release pattern of the drug. obtain. Subsequently, with the decrease in hydroxynaphthoic acid and the increase in oligomers and monomers generated by hydrolysis of the lactic acid-glycolic acid polymer, the release mechanism of bioactive substances with oligomers and monomers as counter ions gradually became dominant, Even when hydroxynaphthoic acid is virtually eliminated from the "composition", stable release of the bioactive substance is maintained. It also explains that the efficiency of incorporation of the physiologically active substance during production of the sustained-release composition can be increased, and that the initial excessive release after administration of the incorporated physiologically active substance can be suppressed.
生理活性ペプチドのヒドロキシナフトェ酸塩を含む徐放性組成物におけるヒ ドロキシナフトェ酸の役割も前記の機構により説明可能である。  The role of hydroxynaphthoic acid in a sustained release composition containing the hydroxynaphthoic acid salt of a physiologically active peptide can also be explained by the above mechanism.
本明細書における 「水不溶性」 とは、 該物質を 40°C以下の温度で、 蒸留水中 で 4時間攪拌したときに、 その溶液 1 L中に溶解する物質の質量が 25mg以下 の場合をいう。  The term "water-insoluble" as used herein means that when the substance is stirred in distilled water at a temperature of 40 ° C or lower for 4 hours, the mass of the substance dissolved in 1 L of the solution is 25 mg or lower. .
本明細書における 「微水溶性」 とは、 上記質量が 25mgより大きく、 5g以 下の場合をいう。 該物質が生理活性物質の塩である場合は、 上記操作において溶 解する生理活性物質の質量をもつて上記定義を適用する。 As used herein, "slightly water-soluble" means that the mass is greater than 25 mg and 5 g or less. Refers to the case below. When the substance is a salt of a physiologically active substance, the above definition is applied with the mass of the physiologically active substance dissolved in the above operation.
本明細書における徐放性組成物の形態は特に限定されないが、 微粒子の形態が 好ましく、 マイクロスフェア （乳酸ーグリコール酸重合体を含む徐放性組成物の 場合はマイクロカプセルとも称する） の形態が特に好ましい。 また、 本明細書に おけるマイクロスフェアとは、 溶液に分散させることができる注射可能な球状の 微粒子のことをいう。 その形態の確認は、 例えば、 走査型電子顕微鏡による観察 で行うことができる。  The form of the sustained release composition in the present specification is not particularly limited, but is preferably in the form of fine particles, and particularly in the form of microspheres (in the case of a sustained release composition containing a lactic acid-glycolic acid polymer, also referred to as microcapsules). preferable. In addition, the microsphere in this specification refers to injectable spherical fine particles that can be dispersed in a solution. The confirmation of the form can be performed, for example, by observation with a scanning electron microscope.
本発明の生理活性物質またはその塩、 ヒドロキシナフトェ酸またはその塩およ び乳酸—グリコール酸重合体またはその塩を含有する徐放性組成物、 例えば、 マ ィクロカプセルの製造法を例示する。  A sustained-release composition containing the physiologically active substance of the present invention or a salt thereof, hydroxynaphthoic acid or a salt thereof, and a lactic acid-glycolic acid polymer or a salt thereof, for example, a method for producing a microcapsule is exemplified. .
( I ) 水中乾燥法  (I) Underwater drying method
( i ) 〇ZW法  (i) ZW method
本方法においては、 まずヒドロキシナフトェ酸またはその塩および乳酸一ダリ コール酸重合体またはその塩の有機溶媒溶液を作製する。 本発明の徐放性製剤の 製造の際に使用する有機溶媒は、 沸点が 1 2 0 °C以下であることが好ましい。 該有機溶媒としては、 例えば、 ハロゲン化炭化水素 （例、 ジクロロメタン、 ク ロロホルム、 ジクロロェタン、 トリクロロェタン、 四塩化炭素等） 、 エーテル類 (例、 ェチルエーテル、 イソプロピルエーテル等） 、 脂肪酸エステル (例、 酢酸 ェチル、 酢酸ブチル等） 、 芳香族炭化水素 （例、 ベンゼン、 トルエン、 キシレン 等） 、 アルコール類 （例えば、 エタノール、 メタノール等） 、 ァセトニトリルな どが用いられる。 乳酸—ダリコール酸重合体またはその塩の有機溶媒としてはな かでもジクロロメタンが好ましい。  In this method, first, an organic solvent solution of hydroxynaphthoic acid or a salt thereof and a polymer of lactic acid-dalicholic acid or a salt thereof is prepared. The organic solvent used for producing the sustained-release preparation of the present invention preferably has a boiling point of 120 ° C. or lower. Examples of the organic solvent include halogenated hydrocarbons (eg, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), fatty acid esters (eg, acetic acid) Examples thereof include ethyl, butyl acetate, etc., aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), and acetonitrile. As an organic solvent for the lactic acid-dalicholate polymer or a salt thereof, dichloromethane is particularly preferable.
ヒドロキシナフトェ酸またはその塩の有機溶媒としては、 なかでもアルコール類 あるいはアルコール類とハロゲン化炭化水素との混液が好ましい。 As the organic solvent of hydroxynaphthoic acid or a salt thereof, alcohols or a mixture of an alcohol and a halogenated hydrocarbon is preferable.
ヒドロキシナフトェ酸またはその塩および乳酸ーグリコール酸重合体または その塩はそれぞれ別個に溶解した後に混合してもよいし、 これらは適宜の割合で 混合された有機溶媒中に 2者を溶解して用いてもよい。 なかでも、 ハロゲン化炭 化水素とアルコール類との混液が好ましく、 特にジクロロメタンとエタノールと の混液が好適である。 Hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof may be separately dissolved and then mixed, or these may be used by dissolving the two in an organic solvent mixed in an appropriate ratio. You may. Among them, halogenated carbon A mixed solution of hydrogen hydride and alcohol is preferred, and a mixed solution of dichloromethane and ethanol is particularly preferred.
ジクロロメタンとの混有機溶媒としてエタノールを用いた場合におけるジク ロロメタンとェタノールとの混有機溶媒中のエタノールの含有率は， 一般的には 約 0. 0 1〜約 5 0 % (v/v；)、 より好ましくは約 0. 0 5〜約 4 0 % (v/v) 、 特に 好ましくは約 0. 1〜約 3 0 % (v/v)から選ばれる。  When ethanol is used as a mixed organic solvent with dichloromethane, the content of ethanol in the mixed organic solvent of dichloromethane and ethanol is generally about 0.01 to about 50% (v / v;). And more preferably from about 0.05 to about 40% (v / v), particularly preferably from about 0.1 to about 30% (v / v).
乳酸一ダリコール酸重合体の有機溶媒溶液中の濃度は、 乳酸一ダリコール酸重 合体の分子量、 有機溶媒の種類によって異なるが、 例えば、 ジクロロメタンを有 機溶媒として用いた場合、 一般的には約 0. 5〜約 7 0重量％ 、 より好ましくは 約 1〜約 6 0重量％ 、 特に好ましくは約 2〜約 5 0重量％から選ばれる。  The concentration of the polymer of lactate-dalicholate in an organic solvent varies depending on the molecular weight of the lactate-dalicholate polymer and the type of organic solvent.For example, when dichloromethane is used as an organic solvent, it is generally about 0%. 5 to about 70% by weight, more preferably about 1 to about 60% by weight, particularly preferably about 2 to about 50% by weight.
ヒドロキシナフトェ酸またはその塩の有機溶媒中の濃度は、 例えばジクロロメ タンとエタノールの混液を有機溶媒として用いた場合、 一般的には約 0. 0 1〜 約 1 0重量％、 より好ましくは約 0 . 1〜約 5重量％、 特に好ましくは約 0 . 5 〜約 3重量％から選ばれる。  The concentration of hydroxynaphthoic acid or a salt thereof in an organic solvent is generally about 0.01 to about 10% by weight, more preferably about 10% by weight, when a mixture of dichloromethane and ethanol is used as the organic solvent. 0.1 to about 5% by weight, particularly preferably about 0.5 to about 3% by weight.
このようにして得られたヒドロキシナフトェ酸またはその塩および乳酸ーグ リコール酸重合体の有機溶媒溶液中に、 生理活性物質またはその塩を添加し、 溶 解あるいは分散させる。 次いで， 得られた生理活性物質またはその塩、 ヒドロキ シナフトェ酸またはその塩および乳酸ーグリコール酸重合体またはその塩から 成る組成物を含む有機溶媒溶液を水相中に加え、 〇 （油相） ZW (水相） ェマル シヨンを形成させた後、 油相中の溶媒を揮散ないしは水相中に拡散させ、 マイク 口カプセルを調製する。 この際の水相体積は、 一般的には油相体積の約 1倍〜約 1 0， 0 0 0倍、 より好ましくは約 5倍〜約 5 0 , 0 0 0倍、 特に好ましくは約 1 0倍〜約 2， 0 0 0倍から選ばれる。  A physiologically active substance or a salt thereof is added to the thus-obtained solution of hydroxynaphthoic acid or a salt thereof and the lactic acid-glycolic acid polymer in an organic solvent, and dissolved or dispersed. Next, an organic solvent solution containing the obtained composition comprising a physiologically active substance or a salt thereof, hydroxysinaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof is added to an aqueous phase, and 〇 (oil phase) ZW ( (Aqueous phase) After the emulsion is formed, the solvent in the oil phase is volatilized or diffused in the aqueous phase to prepare a microcapsule. The volume of the aqueous phase at this time is generally about 1 to about 100,000 times the volume of the oil phase, more preferably about 5 to about 500,000 times, and particularly preferably about 1 to 100,000 times. It is selected from 0 times to about 2,000 times.
上記の外水相中には乳化剤を加えてもよい。 該乳化剤は、 一般に安定な OZW エマルシヨンを形成できるものであればいずれでもよい。 具体的には、 例えば、 ァニオン性界面活性剤 （ォレイン酸ナトリウム、 ステアリン酸ナトリウム、 ラウ リル硫酸ナトリウムなど） 、 非イオン性界面活性剤 （ポリオキシエチレンソルビ タン脂肪酸エステル 〔ツイーン（Tween) 80、 ツイ一ン（Tween) 60、 アトラスパウダ —社〕 、 ポリオキシエチレンヒマシ油誘導体 [HCO- 60, HCO- 50, 日光ケミカル ズ〕 など） 、 ポリビニルピロリドン、 ポリビニルアルコール、 カルボキシメチル セルロース、 レシチン、 ゼラチン、 ヒアルロン酸などが用いられる。 これらの中 の 1種類か、 いくつかを組み合わせて使用してもよい。 使用の際の濃度は、 好ま しくは約 0 . 0 0 0 1〜 1 0重量％の範囲で、 さらに好ましくは約 0 . 0 0 1〜 約 5重量％の範囲で用いられる。 An emulsifier may be added to the above external water phase. Generally, any emulsifier can be used as long as it can form a stable OZW emulsion. Specifically, for example, anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants (polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween 60, Atlas Powder —, Polyoxyethylene castor oil derivatives [HCO-60, HCO-50, Nikko Chemicals] etc.), polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid and the like. One or a combination of these may be used. The concentration at the time of use is preferably in the range of about 0.001 to 10% by weight, more preferably in the range of about 0.001 to about 5% by weight.
上記の外水相中には浸透圧調節剤を加えてもよい。 該浸透圧調節剤としては、 水溶液とした場合に浸透圧を示すものであればよい。  An osmotic pressure regulator may be added to the above external aqueous phase. The osmotic pressure adjusting agent may be any as long as it exhibits an osmotic pressure when used as an aqueous solution.
該浸透圧調節剤としては、 例えば、 多価アルコール類、 一価アルコール類、 単 糖類、 二糖類、 オリゴ糖およびアミノ酸類またはそれらの誘導体などが挙げられ る。  Examples of the osmotic pressure adjusting agent include polyhydric alcohols, monohydric alcohols, monosaccharides, disaccharides, oligosaccharides, amino acids, and derivatives thereof.
上記の多価アルコール類としては、 例えば、 グリセリン等の三価アルコール類、 ァラビ] ル， キシリトール， アド二トール等の五価アルコール類、 マンニトー ル， ソルビトール， ズルシトール等の六価アルコール類などが用いられる。 なか でも、 六価アルコール類が好ましく、 特にマンニトールが好適である。  Examples of the above-mentioned polyhydric alcohols include trihydric alcohols such as glycerin, pentahydric alcohols such as arabiol, xylitol and aditol, and hexahydric alcohols such as mannitol, sorbitol and dulcitol. Can be Of these, hexahydric alcohols are preferred, and mannitol is particularly preferred.
上記の一価アルコール類としては、 例えば、 メタノール、 エタノール、 イソプ 口ピルアルコールなどが挙げられ、 このうちエタノールが好ましい。  Examples of the above monohydric alcohols include methanol, ethanol, isopropyl alcohol and the like, and among them, ethanol is preferable.
上記の単糖類としては、 例えば、 ァラビノース， キシロース， リボース， 2— デォキシリボース等の五炭糖類、 ブドウ糖， 果糖， ガラクト一ス， マンオース， ソルボース， ラムノース， フコース等の六炭糖類が用いられ、 このうち六炭糖類 が好ましい。  Examples of the above-mentioned monosaccharides include pentoses such as arabinose, xylose, ribose and 2-deoxyribose, and hexoses such as glucose, fructose, galactose, manose, sorbose, rhamnose and fucose. Hexasaccharides are preferred.
上記のオリゴ糖としては、 例えば、 マルトトリオース， ラフイノ一ス糖等の三 糖類、 スタキオース等の四糖類などが用いられ、 このうち三糖類が好ましい。 上記の単糖類、 二糖類およびオリゴ糖の誘導体としては、 例えば、 ダルコサミ ン、 ガラクトサミン、 グルクロン酸、 ガラクッロン酸などが用いられる。  As the above-mentioned oligosaccharides, for example, trisaccharides such as maltotriose and raffinose monosaccharide, tetrasaccharides such as stachyose and the like are used, among which trisaccharides are preferable. As the derivatives of the above monosaccharides, disaccharides and oligosaccharides, for example, dalcosamine, galactosamine, glucuronic acid, galacturonic acid and the like are used.
上記のアミノ酸類としては、 L—体のものであればいずれも用いることができ、 例えば、 グリシン、 ロイシン、 アルギニンなどが挙げられる。 このうち L一アル ギニンが好ましい。 これらの浸透圧調節剤は単独で使用しても、 混合して使用してもよい。 As the above amino acids, any L-form amino acid can be used, and examples thereof include glycine, leucine, arginine and the like. Of these, L-arginine is preferred. These osmotic pressure regulators may be used alone or as a mixture.
これらの浸透圧調節剤は、 外水相の浸透圧が生理食塩水の浸透圧の約 1 Z 5 0 〜約 5倍、 好ましくは約 1 Z 2 5〜約 3倍となる濃度で用いられる。  These osmotic pressure adjusting agents are used at a concentration such that the osmotic pressure of the external aqueous phase is about 1 Z50 to about 5 times, preferably about 1 Z25 to about 3 times the osmotic pressure of physiological saline.
有機溶媒を除去する方法としては、 自体公知の方法あるいはそれに準じる方法 が用いられる。 例えば、 プロペラ型撹拌機またはマグネチックスターラーや超音 波発生装置などで撹拌しながら常圧もしくは徐々に減圧にして有機溶媒を蒸発 させる方法、 ロータリーェヴアポレ一夕一などを用いて真空度を調節しながら有 機溶媒を蒸発させる方法、 透析膜を用いて徐々に有機溶媒を除去する方法などが 挙げられる。  As a method for removing the organic solvent, a method known per se or a method analogous thereto is used. For example, a method of evaporating an organic solvent at normal pressure or gradually reducing pressure while stirring with a propeller type stirrer, a magnetic stirrer, an ultrasonic generator, or the like, or a method of reducing the degree of vacuum using a rotary evaporator, etc. There are a method of evaporating the organic solvent while adjusting, and a method of gradually removing the organic solvent using a dialysis membrane.
このようにして得られたマイクロ力プセルは遠心分離または濾過して分取し た後、 マイクロカプセルの表面に付着している遊離の生理活性物質またはその塩、 ヒドロキシナフトェ酸またはその塩、 薬物保持物質、 乳化剤などを蒸留水で数回 繰り返し洗浄し、 再び蒸留水などに分散して凍結乾燥する。  The micro forcepsel obtained in this manner is separated by centrifugation or filtration, and then free bioactive substances or salts thereof, hydroxynaphthoic acid or salts thereof, drugs adhering to the surface of the microcapsules, drugs Wash the retentate, emulsifier, etc. several times with distilled water, disperse again in distilled water, etc., and freeze-dry.
製造工程中、 粒子同士の凝集を防ぐために凝集防止剤を加えてもよい。 該凝集 防止剤としては、例えば、マンニトール， ラクトース， ブドウ糖， デンプン類（例、 コーンスターチ等） などの水溶性多糖、 グリシンなどのアミノ酸、 フイブリン， コラーゲンなどのタンパク質などが用いられる。 なかでも、 マンニトールが好適 である。  During the manufacturing process, an anti-agglomeration agent may be added to prevent aggregation of the particles. Examples of the aggregation inhibitor include water-soluble polysaccharides such as mannitol, lactose, glucose, starches (eg, corn starch), amino acids such as glycine, and proteins such as fibrin and collagen. Of these, mannitol is preferred.
また、 凍結乾燥後、 必要であれば、 減圧下マイクロカプセルが同士が融着しな い条件内で加温してマイクロカプセル中の水分および有機溶媒の除去を行って もよい。 好ましくは、 毎分 1 0〜2 0 °Cの昇温速度の条件下で示差走査熱量計で 求めた乳酸ーグリコール酸重合体の中間点ガラス転移温度よりも若干高い温度 で加温する。 より好ましくは乳酸ーグリコール酸重合体の中間点ガラス転移温度 からこれより約 3 0 高い温度範囲内で加温する。 好ましくは乳酸ーグリコール 酸重合体の中間点ガラス転移温度以上中間点ガラス転移温度より 1 0 °C高い温 度範囲， さらに好ましくは、 中間点ガラス転移温度以上中間点ガラス転移温度よ り 5 "C高い温度範囲で加温する。  After freeze-drying, if necessary, the water and the organic solvent in the microcapsules may be removed by heating under reduced pressure so that the microcapsules do not fuse together. Preferably, the mixture is heated at a temperature slightly higher than the midpoint glass transition temperature of the lactic acid-glycolic acid polymer determined by a differential scanning calorimeter under the condition of a heating rate of 10 to 20 ° C. per minute. More preferably, heating is performed within a temperature range about 30 degrees higher than the midpoint glass transition temperature of the lactic acid-glycolic acid polymer. Preferably, the temperature range is higher than the midpoint glass transition temperature of the lactic acid-glycolic acid polymer by 10 ° C higher than the midpoint glass transition temperature, and more preferably, higher than the midpoint glass transition temperature by 5 "C higher than the midpoint glass transition temperature. Heat in the temperature range.
加温時間はマイクロカプセルの量などによって異なるものの、 一般的にはマイ クロカプセル自体が所定の温度に達した後、 約 1 2時間〜約 1 6 8時間、 好まし くは約 2 4時間〜約 1 2 0時間、 特に好ましくは約 4 8時間〜約 9 6時間である。 加温方法は、 マイクロカプセルの集合が均一に加温できる方法であれば特に限 定されない。 The heating time varies depending on the amount of microcapsules, etc. After the black capsule itself reaches a predetermined temperature, about 12 hours to about 168 hours, preferably about 24 hours to about 120 hours, particularly preferably about 48 hours to about 96 hours It is. The method of heating is not particularly limited as long as the method is capable of uniformly heating the aggregate of microcapsules.
該加温乾燥方法としては、 例えば、 恒温槽、 流動槽、 移動槽またはキルン中で 加温乾燥する方法、 マイクロ波で加温乾燥する方法などが用いられる。 このなか で恒温槽中で加温乾燥する方法が好ましい。  As the heating and drying method, for example, a method of heating and drying in a constant temperature bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like are used. Of these, the method of heating and drying in a thermostat is preferred.
(i i) 法 （1 )  (i i) Law (1)
まず、 乳酸—ダリコール酸重合体またはその塩の有機溶媒溶液を調製する。 該有機溶媒ならびに乳酸一ダリコール酸重合体またはその塩の有機溶媒溶液中 の濃度は、 前記 （I ) ( ί ) 項に記載と同様である。 また混有機溶媒を用いる場 合には、 その両者の比率は、 前記 （I ) ( i ) 項に記載と同様である。  First, an organic solvent solution of a lactic acid-daricholic acid polymer or a salt thereof is prepared. The concentrations of the organic solvent and the lactic acid-dalicholic acid polymer or a salt thereof in the organic solvent solution are the same as those described in the above (I) (ί). When a mixed organic solvent is used, the ratio between the two is the same as described in the above section (I) (i).
このようにして得られた乳酸一グリコール酸重合体またはその塩の有機溶媒 溶液中に、 生理活性物質またはその塩を添加し、 溶解あるいは分散させる。 次い で、 得られた生理活性物質またはその塩と乳酸ーグリコール酸重合体またはその 塩からなる組成物を含む有機溶媒溶液 （油相） にヒドロキシナフトェ酸またはそ の塩の溶液 〔該溶媒としては、 水、 アルコール類 （例、 メタノール、 エタノール 等） の水溶液、 ピリジン水溶液、 ジメチルァセトアミド水溶液等） 〕 を添加する。 この混合物をホモジナイザーまたは超音波等の公知の方法で乳化し、 WZOエマ ルシヨンを形成させる。  A physiologically active substance or a salt thereof is added to an organic solvent solution of the lactic acid-glycolic acid polymer or a salt thereof thus obtained and dissolved or dispersed. Next, a solution of hydroxynaphthoic acid or a salt thereof is added to an organic solvent solution (oil phase) containing a composition comprising the obtained physiologically active substance or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof (as the solvent). Water, an aqueous solution of alcohols (eg, methanol, ethanol, etc.), an aqueous pyridine solution, an aqueous dimethylacetamide solution). This mixture is emulsified by a known method such as a homogenizer or ultrasonic waves to form a WZO emulsion.
次いで， 得られた生理活性物質またはその塩、 ヒドロキシナフトェ酸またはそ の塩および乳酸ーグリコ一ル酸重合体またはその塩から成る wz oエマルショ ンを水相中に加え、 w (内水相） /O (油相） I W (外水相） エマルシヨンを形 成させた後、 油相中の溶媒を揮散させ、 マイクロカプセルを調製する。 この際の 外水相体積は一般的には油相体積の約 1倍〜約 1 0， 0 0 0倍、 より好ましくは 約 5倍〜約 5， 0 0 0倍、 特に好ましくは約 1 0倍〜約 2 , 0 0 0倍から選ばれ る。  Next, a wzo emulsion comprising the obtained physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof is added to an aqueous phase, and w (internal aqueous phase) is added. / O (oil phase) IW (outer water phase) After forming the emulsion, evaporate the solvent in the oil phase to prepare microcapsules. In this case, the volume of the external water phase is generally about 1 to about 100,000 times the oil phase volume, more preferably about 5 to about 5,000 times, particularly preferably about 10 to 100 times. It is selected from double to about 2000 times.
上記の外水相中に加えてもよい乳化剤や浸透圧調節剤、 およびその後の調製法 は前記 （ I ) ( i ) 項に記載と同様である。 Emulsifiers and osmotic pressure regulators that may be added to the above external aqueous phase, and subsequent preparation methods Is the same as described in the above (I) (i).
(iii) W/〇/W法 （2)  (iii) W / 〇 / W method (2)
まず、 ヒドロキシナフトェ酸またはその塩と乳酸ーグリコール酸重合体または その塩の有機溶媒溶液を作成し、 そうして得られた有機溶媒溶液を油相と称する。 該作成法は、 前記 （I) (i) 項に記載と同様である。 あるいは、 ヒドロキシナ フトェ酸またはその塩と乳酸ーグリコール酸重合体をそれぞれ別々に有機溶媒 溶液として作成し、 その後に混合してもよい。 乳酸ーグリコール酸重合体の有機 溶媒溶液中の濃度は、 乳酸ーグリコール酸重合体の分子量、 有機溶媒の種類によ つて異なるが、 例えば、 ジクロロメタンを有機溶媒として用いた場合、 一般的に は約 0.5〜約 70重量％ 、 より好ましくは約 1〜約 60重量％ 、 特に好まし くは約 2〜約 50重量％から選ばれる。  First, an organic solvent solution of hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or a salt thereof is prepared, and the obtained organic solvent solution is referred to as an oil phase. The preparation method is the same as described in the above (I) (i). Alternatively, hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer may be separately prepared as organic solvent solutions, and then mixed. The concentration of the lactic acid-glycolic acid polymer in the organic solvent solution varies depending on the molecular weight of the lactic acid-glycolic acid polymer and the type of the organic solvent.For example, when dichloromethane is used as the organic solvent, it is generally about 0.5 to 0.5%. It is selected from about 70% by weight, more preferably from about 1 to about 60% by weight, particularly preferably from about 2 to about 50% by weight.
次に生理活性物質またはその塩の溶液または分散液 〔該溶媒としては、 水、 水 とアルコール類 （例、 メタノール、 エタノール等） などとの混液〕 を作成する。 生理活性物質またはその塩の添加濃度は一般的には 0. 001 mgZm 1〜 1 0 gZmし ょり好ましくは 0. lmgZm 1〜5 g/m 1で更に好ましくは 1 Om /m 1〜 3 gZm 1である。  Next, a solution or dispersion of a physiologically active substance or a salt thereof is prepared (the solvent is water, a mixture of water and an alcohol (eg, methanol, ethanol, etc.)). The concentration of the physiologically active substance or salt thereof is generally 0.001 mgZm 1 to 10 gZm, preferably 0.1 mgZm 1 to 5 g / m1, more preferably 1 Om / m1 to 3 gZm. Is one.
溶解補助剤、 安定化剤として公知のものを用いてもよい。 生理活性物質や添加 剤の溶解あるいは分散には活性が失われない程度に加熱、 振とう、 撹拌などを行 つてもよく、 そうして得られた水溶液を内水相と称する。  Known dissolution aids and stabilizers may be used. For dissolving or dispersing the physiologically active substance and additives, heating, shaking, stirring and the like may be performed to such an extent that the activity is not lost, and the resulting aqueous solution is referred to as an internal aqueous phase.
上記により得られた内水相と油相とをホモジナイザーまたは超音波等の公知 の方法で乳化し、 WZ〇エマルシヨンを形成させる。  The inner water phase and the oil phase obtained as described above are emulsified by a known method such as a homogenizer or ultrasonic waves to form a WZ emulsion.
混合する油相の体積は内水相の体積に対し、 約 1〜約 1000倍、 好ましくは 約 2〜： L 00倍、 より好ましくは約 3〜10倍である。  The volume of the oil phase to be mixed is about 1 to about 1000 times, preferably about 2 to: L 00 times, more preferably about 3 to 10 times the volume of the internal aqueous phase.
得られた WZOエマルシヨンの粘度範囲は一般的には約 12〜20 で、 約 1 0-10, 000 c pで、 好ましくは約 100〜5, OOOcpである。  The viscosity range of the obtained WZO emulsion is generally about 12-20, about 10-10,000 cp, preferably about 100-5, OOOcp.
次いで， 得られた生理活性物質またはその塩、 ヒドロキシナフトェ酸またはそ の塩および乳酸—グリコール酸重合体またはその塩から成る WZOエマルショ ンを水相中に加え、 w (内水相） /O (油相） I W (外水相） エマルシヨンを形 成させた後、 油相中の溶媒を揮散ないしは外水相中に拡散させ、 マイクロカプセ ルを調製する。 この際の外水相体積は一般的には油相体積の約 1倍〜約 1 0， 0 0 0倍、 より好ましくは約 5倍〜約 5 0 , 0 0 0倍、 特に好ましくは約 1 0倍〜 約 2， 0 0 0倍から選ばれる。 Next, the obtained biologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof, and a WZO emulsion composed of a lactic acid-glycolic acid polymer or a salt thereof are added to an aqueous phase, and w (internal aqueous phase) / O (Oil phase) IW (outer water phase) Form emulsion After the formation, the solvent in the oil phase is volatilized or diffused in the external water phase to prepare a microcapsule. In this case, the volume of the external water phase is generally about 1 to about 100,000 times the oil phase volume, more preferably about 5 to about 500,000 times, and particularly preferably about 1 to 100,000 times. It is selected from 0 times to about 2,000 times.
上記の外水相中に加えてもよい乳化剤や浸透圧調節剤、 およびその後の調製法 は前記 （ I ) ( i ) 項に記載と同様である。  The emulsifiers and osmotic pressure regulators that may be added to the above external aqueous phase, and the subsequent preparation method are the same as those described in the above (I) and (i).
(I I) 相分離法  (I I) Phase separation method
本法によってマイクロカプセルを製造する場合には， 前記 （I ) の水中乾燥法 に記載した生理活性物質またはその塩、 ヒドロキシナフトェ酸またはその塩およ び乳酸ーグリコール酸重合体またはその塩の 3者から成る組成物を含む有機溶 媒溶液にコアセルべーション剤を撹拌下徐々に加えてマイク口ガブセルを析出， 固化させる。 該コアセルべーシヨン剤は油相体積の約 0 . 0 1〜1， 0 0 0倍、 好ましくは約 0 . 0 5〜5 0 0倍、 特に好ましくは約 0 . 1〜2 0 0倍から選ば れる。  When microcapsules are produced by this method, the physiologically active substance or its salt, hydroxynaphthoic acid or its salt, and lactic acid-glycolic acid polymer or its salt described in the above-mentioned (I) in-water drying method can be used. The coacervation agent is gradually added to the organic solvent solution containing the composition comprising the components under stirring to precipitate and solidify the mic-mouth gabcell. The coacervation agent is selected from about 0.01 to 1.0 times, preferably about 0.05 to 500 times, particularly preferably about 0.1 to 200 times the oil phase volume. It is.
コアセルべーシヨン剤としては、 有機溶媒と混和する高分子系， 鉱物油系また は植物油系の化合物等で生理活性物質またはその塩のヒドロキシナフトェ酸ま たはその塩および乳酸ーグリコール酸重合体またはその塩の複合体を溶解しな いものであれば特に限定はされない。 具体的には、 例えば、 シリコン油， ゴマ油， 大豆油， コーン油， 綿実油， ココナッツ油， アマ二油， 鉱物油， n—へキサン， n —ヘプタンなどが用いられる。 これらは 2種類以上混合して使用してもよい。 このようにして得られたマイクロ力プセルを分取した後、 ヘプ夕ン等で繰り返 し洗浄して生理活性物質またはその塩、 ヒドロキシナフトェ酸またはその塩およ び乳酸ーグリコール酸重合体またはその塩からなる組成物以外のコアセルべ一 シヨン剤等を除去し、 減圧乾燥する。 もしくは、 前記 （I ) ( i ) の水中乾燥法 で記載と同様の方法で洗浄を行った後に凍結乾燥、 さらには加温乾燥する。  The coacervation agent may be a high molecular weight compound, a mineral oil type or a vegetable oil type compound or the like which is miscible with an organic solvent, such as a physiologically active substance or its salt, hydroxynaphthoic acid or its salt, and a lactic acid-glycolic acid polymer or There is no particular limitation as long as it does not dissolve the salt complex. Specifically, for example, silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like are used. These may be used as a mixture of two or more. After the micro forcepsel obtained in this way is collected, it is washed repeatedly with heptane or the like, and is washed with a physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof and a lactic acid-glycolic acid polymer or The coacervation agent other than the salt composition is removed and dried under reduced pressure. Alternatively, washing is carried out in the same manner as described in the above-mentioned (I) and (i) in-water drying method, followed by freeze-drying and further heating and drying.
(I I I) 噴霧乾燥法  (I I I) Spray drying method
本法によってマイクロカプセルを製造する場合には， 前記 （I ) の水中乾燥法 に記載した生理活性物質またはその塩、 ヒドロキシナフトェ酸またはその塩およ び乳酸ーグリコール酸重合体またはその塩の 3者を含有する有機溶媒溶液をノ ズルを用いてスプレードライヤー （噴霧乾燥器） の乾燥室内に噴霧し、 極めて短 時間内に微粒化液滴内の有機溶媒を揮発させ、 マイクロカプセルを調製する。 該 ノズルとしては、 例えば、 二流体ノズル型， 圧力ノズル型， 回転ディスク型等が ある。 この後、 必要であれば、 前記 （I ) の水中乾燥法で記載と同様の方法で洗 浄を行った後に凍結乾燥、 さらには加温乾燥してもよい。 水中乾燥法に記載した生理活性物質またはその塩、 ヒドロキシナフトェ酸または その塩および乳酸ーグリコール酸重合体またはその塩を含む有機溶媒溶液を例 えばロータリーェヴアポレーターなどを用いて真空度を調節しながら有機溶媒 および水を蒸発させて乾固した後、 ジェットミルなどで粉砕して微粉末 （マイク 口パーティクルとも称する） としてもよい。 When microcapsules are produced by this method, the physiologically active substance or a salt thereof, hydroxynaphthoic acid or a salt thereof described in the above (I) in-water drying method, and An organic solvent solution containing the lactic acid-glycolic acid polymer or a salt thereof is sprayed into the drying chamber of a spray drier using a nozzle, and the organic matter in the atomized droplets is discharged in a very short time. Evaporate the solvent to prepare microcapsules. Examples of the nozzle include a two-fluid nozzle type, a pressure nozzle type, and a rotating disk type. Thereafter, if necessary, after washing in the same manner as described in the underwater drying method of the above (I), freeze drying and further heating drying may be performed. Adjust the degree of vacuum using an organic solvent solution containing a physiologically active substance or a salt thereof, a hydroxynaphthoic acid or a salt thereof, and a lactic acid-glycolic acid polymer or a salt thereof described in the underwater drying method, for example, using a rotary evaporator. The organic solvent and water may be evaporated to dryness while drying, and then pulverized by a jet mill or the like to form fine powder (also referred to as microparticles).
さらには、 粉枠した微粉末をマイクロカプセルの製造法 （I ) の水中乾燥法で 記載と同様の方法で洗浄を行った後に凍結乾燥、 さらには加温乾燥してもよい。 ここで得られるマイクロカプセルまたは微粉末は使用する乳酸ーグリコール 酸重合体の分解速度に対応した薬物放出が達成できる。  Further, the fine powder in the powder frame may be washed in the same manner as described in the underwater drying method of the microcapsule production method (I), and then freeze-dried, and further, may be heated and dried. The microcapsules or fine powder obtained here can achieve drug release corresponding to the decomposition rate of the lactic acid-glycolic acid polymer used.
本発明の徐放性組成物は、 マイクロスフェア、 マイクロカプセル、 微粉末 （マ イク口パーティクル） など何れの形態であってもよいが、 マイクロカプセルが好 適である。  The sustained-release composition of the present invention may be in any form such as microspheres, microcapsules, and fine powder (microparticles), but microcapsules are preferred.
本発明の徐放性組成物は、 そのまままたはこれらを原料物質として種々の剤形 に製剤化し、 筋肉内、 皮下、 臓器などへの注射剤または埋め込み剤、 鼻腔、 直腸、 子宮などへの経粘膜剤、 経口剤 （例、 カプセル剤 （例、 硬カプセル剤、 軟カプセ ル剤等） 、 顆粒剤、 散剤等の固形製剤、 シロップ剤、 乳剤、 懸濁剤等の液剤等） などとして投与することができる。  The sustained-release composition of the present invention can be formulated as it is or as a raw material into various dosage forms, and can be injected or implanted into intramuscular, subcutaneous, organs, etc., transmucosally into nasal cavity, rectum, uterus, etc. Or oral preparations (eg, capsules (eg, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, liquid preparations such as syrups, emulsions, suspensions, etc.) Can be.
例えば、 本発明の徐放性組成物を注射剤とするには、 これらを分散剤 （例、 ッ ィーン （Tween) 80, HC0— 60等の界面活性剤、 ヒアルロン酸ナトリウム， カルボ キシメチルセルロース， アルギン酸ナトリウム等の多糖類など） 、 保存剤 （例、 メチルパラベン、 プロピルパラベンなど） 、 等張化剤 （例、 塩化ナトリウム， マ ンニトール， ソルビトール， ブドウ糖， プロリンなど） 等と共に水性懸濁剤とす る力 ゴマ油、 コーン油などの植物油と共に分散して油性懸濁剤として実際に使 用できる徐放性注射剤とすることができる。 For example, in order to make the sustained-release composition of the present invention an injection, it is necessary to use a dispersant (eg, a surfactant such as Tween 80, HC0-60, sodium hyaluronate, carboxymethylcellulose, or alginic acid). Polysaccharides such as sodium), preservatives (eg, methylparaben, propylparaben, etc.), tonicity agents (eg, sodium chloride, Aqueous suspension with mannitol, sorbitol, dextrose, proline, etc.) Disperses with vegetable oils such as sesame oil, corn oil, etc. to give sustained-release injections that can be used as oily suspensions. .
本発明の徐放性組成物の粒子径は、 懸濁注射剤として使用する場合には、 その 分散度、 通針性を満足する範囲であればよく、 例えば、 平均粒子径として約 0. ：!〜 300 m、 好ましくは約 0. 5〜150 imの範囲、 さらに好ましくは約 1から 100 mの範囲である。  When the sustained release composition of the present invention is used as a suspension injection, the particle size may be within a range that satisfies the dispersibility and the needle penetration property. ! 300 m, preferably in the range of about 0.5-150 im, more preferably in the range of about 1-100 m.
本発明の徐放性組成物を無菌製剤にするには、 製造全工程を無菌にする方法、 ガンマ線で滅菌する方法、 防腐剤を添加する方法等が挙げられるが、 特に限定さ れない。  In order to make the sustained-release composition of the present invention into a sterile preparation, a method of sterilizing the whole production process, a method of sterilizing with gamma ray, a method of adding a preservative, and the like are mentioned, but are not particularly limited.
本発明の徐放性組成物は、 低毒性であるので、 哺乳動物 （例、 ヒト、 牛、 豚、 犬、 ネコ、 マウス、 ラット、 ゥサギ等） に対して安全な医薬などとして用いるこ とができる。  Since the sustained-release composition of the present invention has low toxicity, it can be used as a drug safe for mammals (eg, humans, cows, pigs, dogs, cats, mice, rats, rabbits, etc.). it can.
本発明の徐放性組成物の投与量は、 主薬である生理活性物質の種類と含量、 剤 形、 生理活性物質放出の持続時間、 対象疾病、 対象動物などによって種々異なる が、 生理活性物質の有効量であればよい。 主薬である生理活性物質の 1回当たり の投与量としては、 例えば、 徐放性製剤が 6力月製剤である場合、 好ましくは、 成人 1人当たり約 0. 0 lmg〜 1 OmgZk g体重の範囲， さらに好ましくは 約 0. 05mg〜5mgZk g体重の範囲から適宜選ぶことができる。  The dosage of the sustained-release composition of the present invention varies depending on the type and content of the physiologically active substance as the main drug, the dosage form, the duration of release of the physiologically active substance, the target disease, the target animal, and the like. Any effective amount may be used. For example, when the sustained-release preparation is a 6-month preparation, the dose of the physiologically active substance as the main drug is preferably in the range of about 0.01 mg to 1 OmgZkg body weight per adult. More preferably, it can be appropriately selected from the range of about 0.05 mg to 5 mgZkg body weight.
1回当たりの徐放性組成物の投与量は、 成人 1人当たり好ましくは、 約 0. 05 mg〜5 OmgZk g体重の範囲、 さらに好ましくは約 0. lmg〜30mgZ k g体重の範囲から適宜選ぶことができる。  The dose of the sustained-release composition per dose is preferably selected from the range of about 0.05 mg to 5 OmgZkg, more preferably about 0.1 mg to 30 mgZ kg, per adult. Can be.
投与回数は、 数週間に 1回、 1か月に 1回、 または数か月 （例、 3力月、 4力月、 6力月など） に 1回等、 主薬である生理活性物質の種類と含量、 剤形、 生理活性 物質放出の持続時間、 対象疾病、 対象動物などによって適宜選ぶことができる。 本発明の徐放性組成物は、 含有する生理活性物質の種類に応じて、 種々の疾患 などの予防 ·治療剤として用いることができるが、 例えば、 生理活性物質が、 L H— RH誘導体である場合には、 ホルモン依存性疾患、 特に性ホルモン依存性癌 (例、 前立腺癌、 子宮癌、 乳癌、 下垂体腫瘍など） 、 前立腺肥大症、 子宮内膜症、 子宮筋腫、 思春期早発症、 月経困難症、 無月経症、 月経前症候群、 多房性卵巣症 候群等の性ホルモン依存性の疾患の予防 ·治療剤、 および避妊 （もしくは、 その 休薬後のリバウンド効果を利用した場合には、 不妊症の予防 '治療） 剤などとし て用いることができる。 さらに、 性ホルモン非依存性であるが L H— R H感受性 である良性または悪性腫瘍などの予防 ·治療剤としても用いることができる。 実施例 The frequency of administration is once every few weeks, once a month, or once every few months (eg, 3rd, 4th, 6th, etc.). And the content, dosage form, duration of release of the physiologically active substance, target disease, target animal, and the like. The sustained-release composition of the present invention can be used as a prophylactic / therapeutic agent for various diseases depending on the type of the physiologically active substance contained therein. For example, the physiologically active substance is an LH-RH derivative. In some cases, hormone-dependent diseases, especially sex hormone-dependent cancers (Eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multi-ovarian ovary It can be used as a prophylactic / therapeutic agent for sex hormone-dependent diseases such as symptomatic groups, and as a contraceptive (or, if the rebound effect after withdrawal is used, for the prevention and treatment of infertility). it can. Furthermore, it can be used as a preventive / therapeutic agent for benign or malignant tumors that are sex hormone-independent but LH-RH sensitive. Example
以下に実施例および実験例をあげて本発明をさらに具体的に説明するが、 これ らは本発明を限定するものではない。  Hereinafter, the present invention will be described more specifically with reference to Examples and Experimental Examples, but these do not limit the present invention.
実施例 1 Example 1
5-oxo-Pro-Hi s-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C2H5 (以下、 ぺプチド Aと 略記する。 武田薬品製） の酢酸塩 1 . 2 gを 1 . 2 mlの蒸留水に溶解した溶液を、 DL-乳酸重合体 （重量平均分子量 4 0 , 6 0 0、 数平均分子量 2 1， 8 0 0、 末 端カルボキシル基量 5 2 . 7 z mo l/g) 4 . 6 2 gおよび 1—ヒドロキシ— 2—ナ フトェ酸 0 . 1 8 gをジクロロメタン 8 . 2 5 mlおよびエタノール 0 . 4 5 m l の混有機溶媒で溶解した溶液と混合してホモジナイザーで乳化し、 W/〇ェマル シヨンを形成した。 次いでこの WZOエマルシヨンを、 予め 15°Cに調節しておい た 0. 1% (w/w)ポリビニルアルコール (EG-40, 日本合成化学製） 水溶液 1200ml中 に注入し、 タービン型ホモミキサーを用いて 7, OOOrpmで攪拌し WZOZWェマル シヨンとした。 この WZOZWエマルシヨンを室温で 3時間撹拌してジクロロメ タンおよびエタノールを揮散ないしは外水相中に拡散させ、 油相を固化させた後、 75 111の目開きの篩いを用いて篩過し、次いで遠心分離機（05PR-22、 日立製作所） を用いて 2, 000ι·ριη、 5分間の条件でマイクロカプセルを沈降させて捕集した。 こ れを再び蒸留水に分散後、 さらに遠心分離を行い、 遊離薬物等を洗浄し、 マイク 口カプセルを捕集した。 捕集されたマイクロカプセルは少量の蒸留水を加えて再 分散しマンニトール 0 . 3 gを添加して溶解した後凍結乾燥して粉末として得ら れた。 マイクロカプセルの質量回収率は 46. 91%、 マイクロカプセル中のペプチド A含量は 18.7%、 1—ヒドロキシ— 2—ナフトェ酸含量は 2.57%であった。 実施例 2 Acetate of 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 (hereinafter abbreviated as peptide A. Takeda Pharmaceutical) 1.2 g Was dissolved in 1.2 ml of distilled water to obtain a DL-lactic acid polymer (weight average molecular weight of 40,600, number average molecular weight of 21,800, terminal carboxyl group of 52.7 z) (mol / g) 4.62 g and 0.18 g of 1-hydroxy-2-naphthoic acid were mixed with a solution of 8.25 ml of dichloromethane and 0.45 ml of ethanol in a mixed organic solvent. The mixture was emulsified with a homogenizer to form a W / emulsion. Next, this WZO emulsion was injected into 1200 ml of a 0.1% (w / w) aqueous solution of polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry) which had been adjusted to 15 ° C in advance, and was then mixed with a turbine homomixer. And stirred at 7, OOOrpm to obtain WZOZW emulsion. This WZOZW emulsion is stirred at room temperature for 3 hours to volatilize dichloromethane and ethanol or diffuse into the external water phase, solidify the oil phase, sieve through a sieve with openings of 75 111, and then centrifuge Using a separator (05PR-22, Hitachi, Ltd.), the microcapsules were settled and collected at 2,000ι · ριη for 5 minutes. This was dispersed again in distilled water, and further centrifuged to wash free drug and the like, and the microcapsules were collected. The collected microcapsules were redispersed by adding a small amount of distilled water, dissolved by adding 0.3 g of mannitol, and freeze-dried to obtain a powder. 46.91% mass recovery of microcapsules, peptide in microcapsules The A content was 18.7%, and the 1-hydroxy-2-naphthoic acid content was 2.57%. Example 2
ペプチド Aの酢酸塩 1. 2gを 1. 2 mlの蒸留水に溶解した溶液を、 DL-乳酸重 合体 （重量平均分子量 40， 600、 数平均分子量 2 1 , 800、 末端カルポキ シル基量 52. 7 mol/g) 4. 62gおよび 3—ヒドロキシー 2—ナフトェ酸 0. 18 gをジクロロメタン 7. 5mlおよびエタノール 0. 45m lの混有機溶媒で 溶解した溶液と混合してホモジナイザーで乳化し、 W/〇エマルシヨンを形成 した。 その後の操作は実施例 1に記載と同様にしてマイクロカプセル粉末を得た。 マイクロカプセルの質量回収率は 53. 18%、 マイクロカプセル中のペプチド A含量は 17. 58%、 3—ヒドロキシ— 2—ナフトェ酸含量は 2. 49%であつ た。 実験例 1  A solution of 1.2 g of peptide A acetate in 1.2 ml of distilled water was added to a DL-lactic acid polymer (weight average molecular weight 40,600, number average molecular weight 21,800, terminal carboxyl group content 52. (7 mol / g) 4.62 g and 0.18 g of 3-hydroxy-2-naphthoic acid were mixed with a solution of 7.5 ml of dichloromethane and 0.45 ml of ethanol in a mixed organic solvent, and emulsified with a homogenizer.マ ル An emulsion was formed. Subsequent operations were performed in the same manner as described in Example 1 to obtain microcapsule powder. The mass recovery of the microcapsules was 53.18%, the content of peptide A in the microcapsules was 17.58%, and the content of 3-hydroxy-2-naphthoic acid was 2.49%. Experimental example 1
実施例 1と 2に記載のマイクロカプセル約 45mgを 0.3mlの分散媒 （0.15 mgの力 ルポキシメチルセルロース， 0.3mgのポリソルべ一ト 80， 15mgのマンニトールを 溶解した蒸留水） に分散して 7週齢雄性 SDラッ卜の背部皮下に 22G注射針で投与し た。 投与から所定時間後にラットを屠殺して投与部位に残存するマイクロカプセ ルを取り出し、 この中のペプチド Aを定量してその初期含量で除して求めた残存 率を表 1に示す。 About 45 mg of the microcapsules described in Examples 1 and 2 were dispersed in 0.3 ml of a dispersing medium (distilled water in which 0.15 mg of lipoxymethylcellulose, 0.3 mg of polysorbate 80, and 15 mg of mannitol were dissolved). Weekly male SD rats were injected subcutaneously into the back of the rat with a 22G needle. After a predetermined time from the administration, the rats were sacrificed and the microcapsules remaining at the administration site were taken out. Peptide A in the microcapsules was quantified and divided by the initial content, and the survival rate obtained is shown in Table 1.
存率：へつノ。 m Presence: Hetsuno. m
残 ナ卜、 A Λ 実施例 1 実施例 Remaining, A Λ Example 1 Example
π no  π no
1曰 9 .7¾  1 says 9.7
乙 74.6¾ 78.8%  Otsu 74.6¾ 78.8%
4週 56.0¾ 58.0%  4 weeks 56.0¾ 58.0%
8週 31.6¾ 36.0%  8 weeks 31.6¾ 36.0%
1 2週 28.3¾ 32.3¾  1 2 weeks 28.3¾ 32.3¾
1 6週 24.5¾ 26.8%  1 6 weeks 24.5¾ 26.8%
2 0週 17.8¾ 23.8¾  20 weeks 17.8¾ 23.8¾
2 6週 12.6¾ 15.6¾ 表 1から明らかなように、 1ーヒドロキシー 2—ナフトェ酸を添加して製造し た実施例 1記載のマイクロカプセルと 3—ヒドロキシー 2—ナフトェ酸を添加 して製造した実施例 2記載のマイクロカプセルとではともに生理活性物質を高 含量に含むことができ、 生理活性物質の初期の過剰放出を非常によく抑止する効 果を併せ持つことがわかる。 そして、 このマイクロカプセルは非常に長期にわた つて生理活性物質を一定速度で放出させることを実現している。 実施例 3  2 6 weeks 12.6¾ 15.6¾ As is clear from Table 1, the microcapsules described in Example 1 manufactured by adding 1-hydroxy-2-naphthoic acid and the manufacturing performed by adding 3-hydroxy-2-naphthoic acid It can be seen that both the microcapsules described in Example 2 can contain a high amount of a physiologically active substance and have an effect of very well suppressing the initial excessive release of the physiologically active substance. These microcapsules have been able to release bioactive substances at a constant rate for a very long time. Example 3
ペプチド Aの酢酸塩 1. 2gを 1. 2 mlの蒸留水に溶解した溶液を、 DL-乳酸重 合体 （重量平均分子量 32， 000、 数平均分子量 1 7， 800、 末端カルボキ シル基量 72. 1 ^mol/g) 4. 62 gおよび 3—ヒドロキシ _ 2 _ナフトェ酸 0. 1 8 gをジクロロメタン 7. 5mlおよびエタノール 0. 45m lの混有機溶媒で 溶解した溶液と混合してホモジナイザーで乳化し、 W/Oエマルションを形成 した。 その後の操作は実施例 1に記載と同様にしてマイクロカプセル粉末を得た。 マイクロカプセルの質量回収率は 5 1. 2%、 マイクロカプセル中のペプチド A 含量は 1 8 . 0 5 、 3—ヒドロキシ— 2—ナフトェ酸含量は 2 . 4 2 ¾であった 実験例 2 A solution of 1.2 g of peptide A acetate dissolved in 1.2 ml of distilled water was added to a DL-lactic acid polymer (weight average molecular weight 32,000, number average molecular weight 17,800, terminal carboxyl group 72. 1 ^ mol / g) 4.62 g and 0.18 g of 3-hydroxy_2-naphthoic acid were mixed with a solution of 7.5 ml of dichloromethane and 0.45 ml of ethanol in a mixed organic solvent, and emulsified with a homogenizer. Thus, a W / O emulsion was formed. Subsequent operations were performed in the same manner as described in Example 1 to obtain microcapsule powder. 51.2% mass recovery of microcapsules, peptide A in microcapsules Experimental Example 2 having a content of 18.05 and a content of 3-hydroxy-2-naphthoic acid of 2.42%
実施例 3記載のマイクロカプセル約 250mgを 1. 5mlの分散媒 （0. 75 mgの力ルポ キシメチルセルロース， 1. 5mgのポリソルべ一ト 80， 75mgのマンニトールを溶解 した蒸留水） に分散してビーグル犬の殿部筋肉内に 22G注射針で投与した。 さら にこのマイクロカプセル約 125mgを 0· 75mlの分散媒 （0. 375 mgのカルポキシメチ ルセルロース， 0. 75mgのポリソルベート 80, 37. 5mgのマンニトールを溶解した蒸 留水） に分散してビーグル犬の殿部皮下に 22G注射針で投与した。 投与から所定 時間後に前腕部静脈より採血し、 血清中べプチド Bの濃度（  Approximately 250 mg of the microcapsules described in Example 3 was dispersed in 1.5 ml of a dispersing medium (0.75 mg of propyloxymethylcellulose, 1.5 mg of polysorbate 80, and distilled water in which 75 mg of mannitol was dissolved). Beagle dogs were dosed intramuscularly with a 22G needle. Further, about 125 mg of the microcapsules were dispersed in 0.75 ml of a dispersing medium (distilled water in which 0.375 mg of carboxymethylcellulose, 0.75 mg of polysorbate 80, and 37.5 mg of mannitol were dissolved), and the beagle dog It was administered subcutaneously to the gluteal area with a 22G injection needle. Blood is collected from the forearm vein at a predetermined time after administration, and serum B peptide B concentration (
を測定した結果を表 2に示す。 Table 2 shows the measurement results.
表 2 Table 2
筋肉内投与 Intramuscular administration
ペプチド A (ng/ml ) —テストステロン（ng/ml)  Peptide A (ng / ml) —Testosterone (ng / ml)
1曰 7. 33 5. 31  1 says 7.33 5.31
2週 0. 76 0. 46  2 weeks 0.76 0.46
4週 0. 91 0. 58  4 weeks 0.91 0.58
8週 3. 65 0. 25以下  8 weeks 3.65 0.25 or less
1 2週 1. 56 0. 25以下  1 2 weeks 1.56 0.25 or less
1 6週 1. 14 0. 25以下  1 week 6 1.14 0.25 or less
2 0週 0. 59 0. 25以下 20 weeks 0.59 0.25 or less
2 6週 0. 53 0. 25以下 2 6 weeks 0.53 0.25 or less
2 8週 0. 48 0. 25以下  2 8 weeks 0.48 0.25 or less
3 0週 0. 33 0. 26  30 weeks 0.33 0.26
3 2週 0. 37 0. 79 3 2 weeks 0.37 0.79
3 4週 0. 22 1. 1 3 4 weeks 0.22 1.1
3 6週 0. 14 0. 94 皮下投与 3 6 weeks 0.14 0.94 Subcutaneous administration
ペプチド A (ng/ml)—テストステロン（ng/ml)  Peptide A (ng / ml) —Testosterone (ng / ml)
1曰 17. 61 2. 79  1 says 17.61 2.79
2週 0. 99 1. 95  2 weeks 0.99 1.95
4週 0. 62 1. 50  4 weeks 0.62 1.50
8週 0. 76 0. 68  8 weeks 0.76 0.68
1 2週 1. 77 0. 25以下  1 2 weeks 1.77 0.25 or less
1 6週 1. 57 0. 25以下  1 week 6 1.57 0.25 or less
2 0週 1. 23 0. 25以下 20 weeks 1.23 0.25 or less
2 6週 1. 93 0. 33 2 6 weeks 1.93 0.33
2 8週 0. 35 1. 59  2 8 weeks 0.35 1.59
3 0週 0. 25 2. 00 表 2から明かのように生理活性物質の血中濃度は約 26週間の長期に渡り維持 されており、 その期間中薬効を示すテストステロン濃度もまた正常値レベル以下 に抑制されており、 約 2 8週から 3 4週では生理活性物質の血中濃度の低下にに 伴い、 テストステロン濃度が正常値に戻りつつあることがわかる。 製剤中にヒド ロキシナフトェ酸を含有しても生理活性物質は、 その活性を損なうことなく長期 にわたつてマイクロカプセル中に安定に存在し、 徐放されていることが明かとな つた。 また投与方法によらず安定した薬効を示すことも明かとなった。 実施例 4  30 week 0.25 2.00 As shown in Table 2, the blood concentration of the physiologically active substance has been maintained for a long period of about 26 weeks, and the testosterone concentration that shows efficacy during that period is also below the normal level. From about week 28 to week 34, testosterone levels are returning to normal values as the blood concentration of the physiologically active substance decreases. It became clear that even if hydroxynaphthoic acid was included in the preparation, the physiologically active substance was stably present in the microcapsules over a long period of time without impairing its activity, and that it was released sustainedly. In addition, it became clear that stable drug efficacy was exhibited regardless of the administration method. Example 4
DL -乳酸重合体 （重量平均分子量 2 8 , 3 0 0、 数平均分子量 1 4， 7 0 0、 ラベル化定量法によるカルボキシル基量 6 9 . 2 mo\/g) 8 6 . 2 gをジクロ口 メタン 6 7 gで溶解した溶液と、 3—ヒドロキシ— 2—ナフトェ酸 9 gをジクロ ロメタン 2 1 0 gおよびエタノール 1 6 . 2 gで溶解した溶液 8 7 . 7 gを混合 して 2 8 . 8 に調節した。 この有機溶媒溶液から 2 1 9 . 2 gを量り取り、 ぺ プチド Aの酢酸塩 20. 4gを 18. 8 gの蒸留水に溶解して 54. 8°Cに加温 した水溶液と混合して 5分間撹拌して粗乳化した後ホモジナイザーを用い、 10, OOOrpm, 5分間の条件にて乳化し WZ〇エマルシヨンを形成した。 次いでこの WZOエマルシヨンを 12. 7 °Cに冷却後に、 予め 12. 7°Cに調節しておいた 0.1% (w/w)ポリビニルアルコール （EG- 40、 日本合成化学製） 水溶液 20リットル 中に 5分 1 1秒で注入し、 H0M0MIC LINE FLOW (特殊機化製） を用いて 9 , OOOrpm で攪拌し W/OZWエマルシヨンとした。 この W/O/Wエマルシヨンを 15 で 30分間温度調整し、 その後 2時間 30分温度調整しないで撹拌してジクロロ メタンおよびエタノールを揮散ないしは外水相中に拡散させ、.油相を固化させた 後、 75 111の目開きの篩いを用いて篩過し、 次いで遠心機 （H- 600S, 国産遠心器 製） を用いて 2， OOOrpmで連続的にマイクロカプセルを沈降させて捕集した。 捕集 されたマイクロ力プセルは少量の蒸留水に再分散し、 90 mの目開きの篩いを用 いて篩過した後マンニトール 12. 3gを添加して溶解した後凍結乾燥して粉末 として得られた。 マイクロカプセル粉末の質量回収量は 84. 4 gで回収率とし ては 75. 7 %であり、 ペプチド A含量は 17. 8%、 3—ヒドロキシ—2—ナ フトェ酸含量は 2. 5%であった。 実施例 5 DL-lactic acid polymer (weight average molecular weight 28,300, number average molecular weight 14,700, carboxyl group content 69.2 mo \ / g by labeling assay) Mouth A solution prepared by dissolving 67 g of methane and 87.7 g of a solution of 9 g of 3-hydroxy-2-naphthoic acid in 210 g of dichloromethane and 16.2 g of ethanol was mixed. Adjusted to 8. From this organic solvent solution, weigh 219.2 g and ぺ Dissolve 20.4 g of peptide A acetate in 18.8 g of distilled water, mix with an aqueous solution heated to 54.8 ° C, stir for 5 minutes to coarsely emulsify, and then use a homogenizer to And emulsified under the conditions of 5 minutes to form WZ〇 emulsion. Then, after cooling the WZO emulsion to 12.7 ° C, it was added to 20 liters of a 0.1% (w / w) aqueous solution of polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical) which had been adjusted to 12.7 ° C in advance. The mixture was injected in 5 minutes and 11 seconds, and stirred at 9, OOO rpm using H0M0MIC LINE FLOW (manufactured by Tokushu Kika) to form a W / OZW emulsion. The temperature of the W / O / W emulsion was adjusted at 15 for 30 minutes, and then stirred for 2 hours and 30 minutes without temperature adjustment to evaporate dichloromethane and ethanol or diffuse them into the external aqueous phase to solidify the oil phase. Thereafter, the microcapsules were sieved using a sieve having an opening of 75111, and then the microcapsules were sedimented continuously at 2, OOO rpm using a centrifuge (H-600S, manufactured by Domestic Centrifuge) and collected. The collected micro force peptide was redispersed in a small amount of distilled water, sieved using a 90-m mesh sieve, added with 12.3 g of mannitol, dissolved, and freeze-dried to obtain a powder. Was. The mass recovery of the microcapsule powder was 84.4 g and the recovery was 75.7%, the peptide A content was 17.8%, and the 3-hydroxy-2-naphthoic acid content was 2.5%. there were. Example 5
DL-乳酸重合体 （重量平均分子量 27, 700、 数平均分子量 15， 700、 ラベル化定量法によるカルボキシル基量 69. 8 ^mol/g) 107. 8gをジクロ ロメタン 83. 9 gで溶解した溶液と、 1—ヒドロキシ一 2 _ナフトェ酸 7. 5 gをジクロロメタン 175. 8 gおよびエタノール 1 3. 5 gで溶解した溶液 1 10. 2 gを混合して 28. 2 °Cに調節した。 この有機溶媒溶液から 274. 2 gを量り取り、 ペプチド Aの酢酸塩 25. 6gを 23. 52 gの蒸留水に溶解し て 52. 4T:に加温した水溶液と混合して 5分間撹拌して粗乳化した後ホモジナ ィザーを用い、 10, 080rpm、 5分間の条件にて乳化し W/〇エマルシヨンを形成し た。 次いでこの W/Oエマルシヨンを 12. 5 X：に冷却後に、 予め 13. 1°Cに 調節しておいた 0. （w/w)ポリビニルアルコール （EG-40、 日本合成化学製） 水 溶液 2 5リットル中に 3分 4 2秒で注入し、 HOMOMIC LINE FLOW (特殊機化製） を用いて 7， OOOrpmで攪拌し WZOZWエマルションとした。 この WZOZWエマ ルシヨンを約 1 5 で 3 0分間温度調整し、 その後 2時間 3 0分温度調整しない で撹拌してジクロロメタンおよびエタノールを揮散な ゝしは外水相中に拡散さ せ、 油相を固化させた後、 の目開きの篩いを用いて篩過し、 次いで遠心機 (H-600S, 国産遠心器製） を用いて 2, OOOrpmで連続的にマイクロカプセルを沈降 させて捕集した。 捕集されたマイクロカプセルは少量の蒸留水に再分散し、 90 / mの目開きの篩いを用いて篩過した後マンニトール 1 5 . 4 gを添加して溶解した 後凍結乾燥して粉末として得られた。 マイクロカプセル粉末の質量回収量は 1 0 5 . 7 gで回収率としては 7 5 . 8 %であり、 ペプチド A含量は 1 8 . 4 ¾、 1 ーヒドロキシ— 2 _ナフトェ酸含量は 2 . 8 %であった。 実施例 6 DL-lactic acid polymer (Weight average molecular weight 27,700, Number average molecular weight 15,700, Carboxyl group content by labeling assay 69.8 ^ mol / g) 107.8 g Dissolved in 83.9 g of dichloromethane Then, 7.5 g of 1-hydroxy- 12-naphthoic acid and 11.2 g of a solution of 175.8 g of dichloromethane and 13.5 g of ethanol were mixed to adjust the temperature to 28.2 ° C. From the organic solvent solution, weigh 274.2 g, dissolve 25.6 g of peptide A acetate in 23.52 g of distilled water, mix with an aqueous solution warmed to 52.4 T :, and stir for 5 minutes. The mixture was roughly emulsified and then emulsified using a homogenizer under the conditions of 10,080 rpm for 5 minutes to form a W / 〇emulsion. Then, the W / O emulsion was cooled to 12.5 X: and then adjusted to 13.1 ° C in advance. 0.1 (w / w) polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical) water The solution was injected into 25 liters for 3 minutes and 42 seconds and stirred at 7, OOO rpm using HOMOMIC LINE FLOW (manufactured by Tokushu Kika) to form a WZOZW emulsion. The WZOZW emulsion was heated at a temperature of about 15 for 30 minutes, and then stirred for 2 hours and 30 minutes without temperature adjustment to evaporate dichloromethane and ethanol, and then diffused into the external water phase to disperse the oil phase. After solidifying, the microcapsules were sieved using a sieve with a mesh opening, and then the microcapsules were continuously sedimented at 2, OOO rpm using a centrifuge (H-600S, manufactured by Domestic Centrifuge) and collected. The collected microcapsules were re-dispersed in a small amount of distilled water, sieved using a sieve with a 90 / m mesh, added with 15.4 g of mannitol, dissolved, and freeze-dried to obtain a powder. Obtained. The mass recovery of the microcapsule powder was 105.7 g with a recovery of 75.8%, the peptide A content was 18.4%, and the 1-hydroxy-2-naphthoic acid content was 2.8%. Met. Example 6
DL -乳酸重合体 （重量平均分子量 3 0， 8 0 0、 数平均分子量 1 3， 9 0 0、 ラベル化定量法によるカルボキシル基量 6 6 . 3 /zmol/g) 1 0 7 . 9 gをジクロ ロメタン 8 3 . 3 gで溶解した溶液と、 1ーヒドロキシ— 2—ナフトェ酸 7 . 5 gをジクロロメタン 1 7 5 gおよびエタノール 1 3 . 5 gで溶解した溶液 1 0 9 . 7 gを混合して 2 8 . 71に調節した。 この有機溶媒溶液から 2 7 4. 3 gを量 り取り、 ペプチド Aの酢酸塩 2 4. 8 98を2 3 . 4 9 gの蒸留水に溶解して 5 1 . 2 °Cに加温した水溶液と混合して 5分間撹拌して粗乳化した後ホモジナイザ —を用い、 10, 070ι·ρπκ 5分間の条件にて乳化し W/Oエマルシヨンを形成した。 次いでこの WZOエマルシヨンを 1 2 . 8 °Cに冷却後に、 予め 1 3 . 3 に調節 しておいた 0. （w/w)ポリビニルアルコール （EG- 40、 日本合成化学製） 水溶液 2 5リツトル中に 4分 1 3秒で注入し、 HOMOMIC LINE FLOW (特殊機化製） を用 いて 7, OOOrpmで攪拌し WZO/Wエマルシヨンとした。 この W/OZWエマルシ ヨンを約 1 5 で 3 0分間温度調整し、 その後 2時間 3 0分温度調整しないで撹 拌してジクロロメタンおよびエタノールを揮散ないしは外水相中に拡散させ、 油 相を固化させた後、 75 mの目開きの篩いを用いて篩過し、次いで遠心機（H - 600S, 国産遠心器製） を用いて 2, OOOrpmで連続的にマイクロカプセルを沈降させて捕集 した。 捕集されたマイクロカプセルは少量の蒸留水に再分散し、 90 ^ mの目開き の篩いを用いて篩過した後マンニトール 1 5 . 4 gを添加して溶解した後凍結乾 燥して粉末として得られた。 マイクロカプセル粉末の質量回収量は 1 0 1 . 9 g で回収率としては 7 3 . 1 %であり、 ペプチド A含量は 1 7 . 3 %, 1—ヒドロ キシ— 2—ナフトェ酸含量は 2 . 9 %であった。 実験例 3 DL-lactic acid polymer (weight average molecular weight 30,800, number average molecular weight 13,900, amount of carboxyl group by labeling assay 66.3 / zmol / g) A solution prepared by dissolving 83.3 g of dichloromethane in 7.5 g of 1-hydroxy-2-naphthoic acid was mixed with 19.7 g of a solution obtained by dissolving 7.5 g of dichloromethane and 13.5 g of ethanol. It was adjusted to 28.71. From this organic solvent solution, 274.3 g was weighed, and the peptide A acetate 24.898 was dissolved in 23.49 g of distilled water and heated to 51.2 ° C. The resulting mixture was mixed with an aqueous solution, stirred for 5 minutes, coarsely emulsified, and then emulsified using a homogenizer under the conditions of 10,070ι · ρπκ for 5 minutes to form a W / O emulsion. Next, the WZO emulsion was cooled to 12.8 ° C, and then adjusted to 13.3 in advance in 25 liters of an aqueous (w / w) polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical) aqueous solution. The mixture was injected in 4 minutes and 13 seconds, and stirred at 7, OOO rpm using HOMOMIC LINE FLOW (manufactured by Tokushu Kika) to form a WZO / W emulsion. This W / OZW emulsion was temperature-adjusted at about 15 to 30 minutes, and then stirred for 2 hours and 30 minutes without temperature adjustment to allow dichloromethane and ethanol to evaporate or diffuse into the external aqueous phase to solidify the oil phase. After sieving, it is sieved using a 75 m sieve with an opening, and then centrifuged (H-600S, Microcapsules were sedimented continuously at 2, OOOrpm using a domestic centrifuge and collected. The collected microcapsules were redispersed in a small amount of distilled water, sieved using a sieve with a 90-m opening, added with 15.4 g of mannitol, dissolved, and freeze-dried to obtain a powder. Was obtained as The mass recovery of the microcapsule powder was 101.9 g, the recovery was 73.1%, the peptide A content was 17.3%, and the 1-hydroxy-2-naphthoic acid content was 2. 9%. Experiment 3
実施例 5と 6に記載のマイクロカプセル約 45mgを 0. 3mlの分散媒 （0. 1 5 mgの力 ルポキシメチルセルロース， 0. 3mgのポリソルベート 80, 1 5mgのマンニトールを 溶解した蒸留水） に分散して 7週齢雄性 SDラッ卜の背部皮下に 22G注射針で投与し た。 投与から所定時間後にラットを屠殺して投与部位に残存するマイクロカプセ ルを取り出し、 この中のペプチド Aを定量してその初期含量で除して求めた残存 率を表 3に示す。  About 45 mg of the microcapsules described in Examples 5 and 6 were dispersed in 0.3 ml of a dispersing medium (0.1 mg of rupoxymethylcellulose, 0.3 mg of polysorbate 80, and 15 mg of mannitol in distilled water). A 7-week-old male SD rat was subcutaneously administered to the back of the rat with a 22G needle. At a predetermined time after the administration, the rats were sacrificed, and the microcapsules remaining at the administration site were taken out. Peptide A in the microcapsules was quantified and divided by the initial content.
表 3 Table 3
残存率：ペプチド A Residual rate: peptide A
実施例 5 実施例 6  Example 5 Example 6
1曰 87. 0¾ 90. 5¾  1 says 87.0¾ 90.5¾
1週 80. 0% 83. 2%  1 week 80. 0% 83.2%
2週 72. 3¾ 73. 5¾  2 weeks 72. 3¾ 73. 5¾
4週 57. 6% 58. 0¾  4 weeks 57. 6% 58. 0¾
8週 48. 2% 46. 7%  8 weeks 48. 2% 46.7%
1 2週 34. 5¾ 32. 8¾  1 2 weeks 34. 5¾ 32. 8¾
1 6週 23. 1¾ 22. 0¾  1 6 weeks 23. 1¾ 22. 0¾
2 0週 14. 7¾ 13. 4¾  20 weeks 14.7¾ 13.4¾
2 6週 6. 1% 3. 3¾ 表 3から明らかなように、 1 —ヒドロキシ— 2—ナフトェ酸を添加して製造し た実施例 5および 6記載のマイクロカプセルは基剤である乳酸重合体の分子量 は異なるが、 ともに約 125 gのスケールで製造しても生理活性物質を高含量に含 むことができ、 生理活性物質の初期の過剰放出を非常によく抑止する効果を併せ 持つことがわかる。 そして、 このマイクロカプセルは非常に長期にわたって生理 活性物質を一定速度で放出させることを実現している。 産業上の利用可能性 2 6 weeks 6. 1% 3. 3¾ As is clear from Table 3, it was manufactured by adding 1-hydroxy-2-naphthoic acid. Although the microcapsules described in Examples 5 and 6 differ in the molecular weight of the lactic acid polymer as the base, they can contain a high amount of a bioactive substance even when manufactured on a scale of about 125 g. It can be seen that it has the effect of very well suppressing the initial excessive release of the substance. These microcapsules have been able to release bioactive substances at a constant rate for a very long time. Industrial applicability
本発明の徐放性組成物は生理活性物質を高含量で含有し、 かつその初期過剰放 出を抑制し長期にわたる（好ましくは約 6ヶ月以上）安定した放出速度を実現す ることができる。  The sustained-release composition of the present invention contains a high content of a physiologically active substance, suppresses the initial excessive release, and can realize a stable release rate over a long period (preferably about 6 months or more).

Claims

請 求 の 範 囲 The scope of the claims
I. 生理活性物質またはその塩、 ヒドロキシナフトェ酸またはその塩および乳酸 I. Physiologically active substance or its salt, hydroxynaphthoic acid or its salt and lactic acid
—ダリコール酸重合体またはその塩を含有し、 該乳酸—ダリコール酸重合体の重 量平均分子量と該乳酸一グリコール酸重合体の単位質量 （グラム） 当たりの末端 の力ルポキシル基量 （マイクロモル） との積が 1, 200， 000以上 3, 00 0 , 000以下である徐放性組成物。 -Containing a polymer of dalicholate or a salt thereof, the weight average molecular weight of the lactic acid-dalicholate polymer and the amount of terminal lipoxyl groups per unit mass (gram) of the lactic acid-glycolic acid polymer (micromol) , The product of which is not less than 1,200,000 and not more than 3,00,000.
2. 生理活性物質が生理活性べプチドである請求項 1記載の徐放性組成物。 2. The sustained-release composition according to claim 1, wherein the bioactive substance is a bioactive peptide.
3. 生理活性物質が LH-RH誘導体である請求項 1記載の徐放性組成物。 3. The sustained-release composition according to claim 1, wherein the physiologically active substance is an LH-RH derivative.
4. ヒドロキシナフトェ酸が 1—ヒドロキシー 2—ナフトェ酸または 3—ヒドロ キシー 2—ナフトェ酸である請求項 1記載の徐放性組成物。 4. The sustained-release composition according to claim 1, wherein the hydroxynaphthoic acid is 1-hydroxy-2-naphthoic acid or 3-hydroxy-2-naphthoic acid.
5. ヒドロキシナフトェ酸が 1ーヒドロキシ— 2 _ナフ卜ェ酸である請求項 1記 載の徐放性組成物。  5. The sustained-release composition according to claim 1, wherein the hydroxynaphthoic acid is 1-hydroxy-2-naphthoic acid.
6. 乳酸ーグリコール酸重合体の組成モル％が 10070〜40ノ60である請 求項 1記載の徐放性組成物。  6. The sustained-release composition according to claim 1, wherein the composition mol% of the lactic acid-glycolic acid polymer is 10070 to 40-60.
7. 乳酸ーグリコール酸重合体の組成モル％が 100Z0である請求項 1記載の 徐放性組成物。  7. The sustained-release composition according to claim 1, wherein the composition mol% of the lactic acid-glycolic acid polymer is 100Z0.
8. 重合体の重量平均分子量が約 3， 000〜約 100, 000である請求項 1 記載の徐放性組成物。  8. The sustained release composition according to claim 1, wherein the weight average molecular weight of the polymer is from about 3,000 to about 100,000.
9. 重量平均分子量が約 20, 000〜 50， 000である請求項 8記載の徐放 性組成物。 9. The sustained-release composition according to claim 8, wherein the weight-average molecular weight is about 20,000 to 50,000.
10. LH- RH誘導体が式  10. LH-RH derivative has the formula
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
[式中、 Yは DLeu、 DAI a, DTrp、 DSer(tBu)、 D2Nalまたは DHis (ImBzl)を示し、 Zは H- C2H5または Gly-NH2を示す。 ]で表されるペプチドである請求項 3記載の徐放性 組成物。 [In the formula, Y is DLeu, DAI a, DTrp, DSer (tBu), shows the D2Nal or DHis (ImBzl), Z represents an H- C 2 H 5 or Gly-NH 2. 4. The sustained-release composition according to claim 3, which is a peptide represented by the formula:
I I. 重合体の末端のカルボキシル基量が重合体の単位質量 （グラム） あたり 50〜 90マイク口モルである請求項 1記載の徐放性組成物。 I I. The sustained-release composition according to claim 1, wherein the amount of the carboxyl group at the terminal of the polymer is 50 to 90 micole moles per unit mass (gram) of the polymer.
1 2 . ヒドロキシナフトェ酸またはその塩と LH-RH誘導体またはその塩のモル 比が 3対 4ないし 4対 3である請求項 3記載の徐放性組成物。 12. The sustained-release composition according to claim 3, wherein the molar ratio of hydroxynaphthoic acid or a salt thereof to an LH-RH derivative or a salt thereof is 3: 4 to 4: 3.
1 3 . 徐放性組成物中、 LH- RH誘導体またはその塩が 1 2 % (w/w)から 2 4 % (w/w)含有される請求項 3記載の徐放性組成物。 13. The sustained-release composition according to claim 3, wherein the LH-RH derivative or a salt thereof is contained in the sustained-release composition in an amount of 12% (w / w) to 24% (w / w).
1 4. 生理活性物質またはその塩が微水溶性または水溶性である請求項 1記載 の徐放性組成物。 1 4. The sustained-release composition according to claim 1, wherein the physiologically active substance or a salt thereof is slightly water-soluble or water-soluble.
1 5 . 注射用である請求項 1記載の徐放性組成物。  15. The sustained-release composition according to claim 1, which is for injection.
1 6 . 生理活性物質またはその塩、 乳酸ーグリコール酸重合体またはその塩お よびヒドロキシナフトェ酸またはその塩の混合液から溶媒を除去することを特 徵とする請求項 1記載の徐放性組成物の製造法。  16. The sustained-release composition according to claim 1, wherein the solvent is removed from a mixture of a physiologically active substance or a salt thereof, a lactic acid-glycolic acid polymer or a salt thereof, and hydroxynaphthoic acid or a salt thereof. Manufacturing method of goods.
1 7 . 乳酸ーグリコール酸重合体またはその塩およびヒドロキシナフトェ酸ま たはその塩を含有する有機溶媒溶液に生理活性物質またはその塩を混合、 分散し、 次いで有機溶媒を除去することを特徴とする請求項 1 6記載の製造法。  17. A bioactive substance or a salt thereof is mixed and dispersed in an organic solvent solution containing a lactic acid-glycolic acid polymer or a salt thereof and hydroxynaphthoic acid or a salt thereof, and then the organic solvent is removed. 17. The production method according to claim 16, wherein
1 8 . 生理活性物質またはその塩が生理活性物質またはその塩を含有する水溶 液である請求項 1 6記載の製造法。  18. The method according to claim 16, wherein the physiologically active substance or a salt thereof is an aqueous solution containing the physiologically active substance or a salt thereof.
1 9 . 生理活性物質の塩が遊離塩基または酸との塩である請求項 1 6記載の製 造法。  19. The process according to claim 16, wherein the salt of the physiologically active substance is a salt with a free base or an acid.
2 0 . 請求項 1記載の徐放性組成物を含有してなる医薬。  20. A medicament comprising the sustained-release composition according to claim 1.
2 1 . 請求項 3記載の徐放性組成物を含有してなる前立腺癌、 前立腺肥大症、 子宮内膜症、 子宮筋腫、 子宮線維腫、 思春期早発症、 月経困難症もしくは乳癌の 予防、 治療剤または避妊剤。 21. Prevention of prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroids, puberty onset, dysmenorrhea or breast cancer comprising the sustained release composition according to claim 3. Therapeutic or contraceptive.
2 2 . 少なくとも約 6ヶ月以上にわたって生理活性物質またはその塩を放出する 請求項 1記載の徐放性組成物。  22. The sustained release composition according to claim 1, which releases a physiologically active substance or a salt thereof for at least about 6 months or more.
2 3 . 生理活性物質またはその塩、 1 —ヒドロキシ— 2 —ナフトェ酸またはそ の塩および生体内分解性ポリマーまたはその塩を含有してなる徐放性組成物。  23. A sustained-release composition comprising a physiologically active substance or a salt thereof, 1-hydroxy-2-naphthoic acid or a salt thereof, and a biodegradable polymer or a salt thereof.
PCT/JP2000/004683 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof WO2001005380A1 (en)

Priority Applications (16)

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BR0012400-1A BR0012400A (en) 1999-07-15 2000-07-13 Continuous release composition, method for producing sustained release composition, medicament, and prophylactic or therapeutic agent
DE60034568T DE60034568T2 (en) 1999-07-15 2000-07-13 RELATED RELEASE COMPOSITIONS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE
US10/019,786 US7265157B1 (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof
SK34-2002A SK342002A3 (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof
HU0202880A HUP0202880A3 (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof
NZ516466A NZ516466A (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof
KR1020027000546A KR20020012312A (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof
PL00352499A PL352499A1 (en) 1999-07-15 2000-07-13 Compositions of prolonged active substance release, method of obtaining them and their applications
AU58530/00A AU5853000A (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof
IL14741700A IL147417A0 (en) 1999-07-15 2000-07-13 Sustained release compositions, methods for producing the same and uses thereof
CA002378714A CA2378714A1 (en) 1999-07-15 2000-07-13 Sustained release compositions, methods for producing the same and uses thereof
EP00944418A EP1197208B1 (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof
MXPA02000461A MXPA02000461A (en) 1999-07-15 2000-07-13 Sustained release compositions, process for producing the same and use thereof.
NO20020084A NO20020084L (en) 1999-07-15 2002-01-08 Sustained release compositions, processes for their preparation, and their use
HK02103567.5A HK1042237A1 (en) 1999-07-15 2002-05-11 Sustained release compositions, process for producing the same and use thereof
US11/782,707 US20080014237A1 (en) 1999-07-15 2007-07-25 Sustained release compositions, process for producing the same and use thereof

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JP11/201887 1999-07-15
JP20188799 1999-07-15

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CA (1) CA2378714A1 (en)
CZ (1) CZ2002114A3 (en)
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HK (1) HK1042237A1 (en)
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EP1197208A1 (en) 2002-04-17
IL147417A0 (en) 2002-08-14
DE60034568D1 (en) 2007-06-06
BR0012400A (en) 2002-05-21
HUP0202880A2 (en) 2003-01-28
US7265157B1 (en) 2007-09-04
EP1197208B1 (en) 2007-04-25
DE60034568T2 (en) 2008-01-03
KR20020012312A (en) 2002-02-15
NZ516466A (en) 2003-02-28
NO20020084D0 (en) 2002-01-08
CZ2002114A3 (en) 2002-04-17
ATE360413T1 (en) 2007-05-15
HUP0202880A3 (en) 2003-04-28
HK1042237A1 (en) 2002-08-09
RU2002103718A (en) 2003-10-10
CN1361685A (en) 2002-07-31
AU5853000A (en) 2001-02-05
EP1197208A4 (en) 2004-06-30
PL352499A1 (en) 2003-08-25
SK342002A3 (en) 2002-05-09
CA2378714A1 (en) 2001-01-25
NO20020084L (en) 2002-03-14
ZA200200347B (en) 2003-03-26
US20080014237A1 (en) 2008-01-17
MXPA02000461A (en) 2002-07-30

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